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Dec 31
Two mice; the mouse on the left has more fat s...
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Lifestyle diseases are the ones we induce on ourselves by how we live our lives. They include being overweight/obese, insulin resistance, metabolic syndrome, type II diabetes (really a spectrum here), all leading to increased cardiovascular disease (and a number of other deadly diseases such as cancer, but to a lesser amount).

The easy solution to all of these is simple lifestyle changes – exercise and healthy eating. However, despite the well known ‘simple’, virtually no cost solutions most people fail. They want their cake and eat it too. They want to be healthy but they do not want to actually do anything about it.

A new paper might offer a potential solution.

Morino et. al., 2008 (PLOS one: freely available) examined if mild electrical stimulation (MES) combined with heat shock (HS) (not as bad as it sounds) could alleviate insulin resistance and obesity in a mouse model of diabetes.

Previous research with direct-field electrical stimulation have demonstrated decreased inflammation, better bone healing, reduction in pain, and inhibition of tumor growth (so don’t think of cell phones and electrical lines in this context of electrical stimulation) (see introduction of paper).

Experiment:

Twice a week the animals received 10 minutes of treatment (12 V (0.1 ms pulse duration) together with ‘heat shock’ at 42 degrees Celsius),(just for your information a hot tub is usually in the 38 to 40 range) or the individual treatments by themselves for a 12 – 15 week period. The researchers point out that the electrical simulations were ‘well tolerated and did not cause pain or annoyance behavior in the mice’ – the animals would sit still or doze off.

Two different strains of mice were used. One was fed a high-fat diet (which is typical for these types of paradigms) and in the other a leptin receptor deficiency causes them to overeat, and within one week after the initiation of the diet the treatment would start.

After 12 weeks on the diet (and treatment) the mice receiving the HS or the HS + MES had lower fasting glucose levels compared to the control group. However, fasted insulin levels were not lower in the HS group compared to controls, but the HS + MES group did have lower levels. In a glucose tolerance test (insulin sensitivity test) the HS + MES group had better glucose tolerance (quicker removal from blood stream) than the other groups. Another test for insulin resistance (HOMA-IR index – which is really fasting blood glucose x fasting insulin/22.5) was also significantly improved in the combined treated group.

Food intake or body weight did not differ between all the groups. Meaning that the treatment did not cause the animals to eat less – thereby the treatment positive effects are not simply due to a reduction of food intake.

They basically repeated the study for a longer period of time (25 weeks) to see if it would work in the more chronic setting. The combined treatment produced all the same results and additionally reduced the levels of TNF-alpha.

They also found that the serum levels of adiponectin (an adipocytokine secreted by fat tissue) were increased in the treated rats. Adiponectin is widely recognized to be inversely correlated with the amount of fat. Therefore, the researchers decided to investigate the amount of adipose tissue in the groups. White adipose tissue was reduced in the combined treated animals compared to the controls along with a reduction in the cell size of the adipocytes. More importantly visceral fat was decreased. Additionally, the brown fat (which burns calories to produce heat – called thermogenesis) expression of uncoupling protein one (UCP-1) was increased in the combined treated group, which would help explain the overall results.

In a second model of type II diabetes db/db mice (leptin receptor deficiency so they become obese) were used and the same overall results observed.

Interestingly, and intriguing is they tried the same treatment in standard fed mice which do not develop obesity and reported no differences in any of the above mentioned measurements (e.g. fasting glucose, insulin) between the control group and the HS + MES group.

They further tested which pathways they think the treatment is working through but I won’t go into those details here, but will present the authors summary of this part:

The effect of HS+MES on insulin signaling is likely through the capacity of electrical signal to trigger the activation of Akt (Fig. 8, [8]) and of HS to up-regulate Hsp72, which in turn inhibits JNK and activates the insulin signaling pathway (Fig. 4C, Fig. 9 [24,41]). Although the core body temperature of the mice was less than 42 C, the method of mild HS that we used was enough to induce the expression of Hsp72 (Fig. 4D).

One caveat:

The HS + MES treatment started within one week after the initiation of the high fat diet. We do not know if this treatment would ‘reverse’ the effect if started in the normal human situation – after they have become obese and insulin resistance or diabetic. However, in the db/db mice because of the genetic reduction in leptin receptor it could be argued the animals are on their way already when the treatment started (but I am not familiar enough with this transgenic strain to fully comment).

An interesting experiment would be too test this treatment further along the progression of insulin resistance/diabetes/obesity. But we know exercise and serious changes in diet can have dramatic effects on these conditions, so it is still possible that the HS + MES could work even if started after the condition is full blow – but it wasn’t tested in this paper.

Could we translate this to humans?

The authors point out the low levels of electrical stimulation as well as heat shock are used in the clinical setting. However, I would point out in both of these situations (from the references I read) the treatments were for relatively short time periods. In the treatment outlined above for the human situation, assuming the individuals are going to continue with an unhealthy lifestyle it would suggest they would have to continue with the treatment indefinitely. The long term health consequence would have to be studied – but it appears to be positive based on the above results as the animals were treated for a relatively long period of time (and no negative effects observed in the normally fed animals – but also no positive effects).

Of course in reality the goal is to live a healthy lifestyle so you do not develop these lifestyle linked diseases – but if you are unable to live a healthy lifestyle this might an option in the future – but it should be a last action of last resort.

Dec 30
Rockefeller Center ice rink
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It is easy to get into an equilibrium – a stasis. The question is how to perturb the system to get of this this state?

Wow — or something close to that. I might not even have the right word here. What I am looking for is when you are walking along in slippery conditions and your feet suddenly slip out from underneath you and your brain goes wo…. Like what the hell happened to me – and by the time your brain has said wo… it has already caught itself from falling.

This morning (as a metaphor):

In Vancouver where I live after much snow (at least for us) followed by a thawing and plenty of rain it started to freeze and the streets and sidewalks are now like one giant skating rink. Every X number of steps all of a sudden your feet start flying from underneath you and your brain goes – Wo… .  Somewhere deep within your cerebellum (among other areas) the brain is jolted into trying to maintain an upright stance (first degree wo…). It doesn’t always work and sometimes your feet keep going upwards and your heads plummets towards good old mother earth (covered with cement and pavement – good old human-kind). Your old noggin smacks hard against the world (second degree wo…), and head wounds tend to really bleed. It doesn’t take much blood spilling from your head to cause serious alarm – but really it is not that much in terms of your blood reserves. You just had a serious mind slippage – and barring a traumatic brain injury (which is a serious problem) maybe you are better off for the experience. You just had a super wo… experience. Once you wipe away the blood you might even have an epiphany of some sort. Now I am not arguing that we should aim for these more traumatic brain slips.

Even the initial wo.. slippage and correction I think is good for your brain. Your brain has been perturbed and you needed (or at least your brain – because the body adjustment were probably at a non-conscious level) to made serious adjustments to keep you upright. It is like practicing balancing – but also inducing some brain plasticity to be better in the future.

From physical to mental:

But beyond the physicallity of a simple slip on ice it is good for your brain health to have mind slippage – exposure to new thoughts and ideas. If you are just  repeatedly reading the dogma of your chosen field I would argue you are not really learning.

Now you probably can not on purpose slip just like it is nearly impossible to tickle yourself – but others can tickle you. Go find some ice, expose yourself to new people be it in person or by what information you take in (books, blogs, articles, etc).

Over the last two evening I experienced serious mind slippage (wo..) reading about the problem of poverty – and maybe how to fix it (and it the last couple weeks had a second degree brain slippage – but that is too gory to go into here). In another post I will share the information of my recent first degree mind slippage and what I have learned about the poverty problem – and potential solution.

Take home message:

Go find ice – mental and physical ice to induce slippage and the wo… experience. Grow.

Dec 29

During the seasonal celebrations I think it can be wise to reflect a bit about life – to improve our brain health. One way to attempt this is by asking yourself what you are thankful for? Here are just a few examples of what I am thankful for (including the mundane).

Family and Friends:

I am thankful for my family and friends. Family, because of love and our evolutionary link. Friends, because of love and the sharing of thoughts and ideas.

This brings up a recent conversation that came up one evening about what is a friend? Is someone a friend because they are on your facebook list? Possibly but not necessarily. I think there is a closeness distribution of friendships – not all friends do we think of as the same. Individuals have different definitions of how we classify friendship. Some say they only have 4 friends while others say 50, 100 or more. I would think there are basic differences in how many friends you make, but also how you define what a friend is. That aside, no matter how you define them – be thankful for your friends.

Recent studies suggest that the happiness of your friends have a relatively large influence on your happiness. Additionally, it appears that being overweight or obese is also influenced by the weight of your friends (see here for a piece that covers how friendships influence both the happiness and obesity). both negative and positive attributions appear to be ‘contagious’ among your social networks. If your friends can influence your happiness then I think there (yours) enthusiasm, drive, kindness, optimism, world-view, hopefulness could also spread among friendship networks.

What are you spreading among our friendship networks?

The everyday consumer things:

I am also thankful for a thing most of us take for granted – the shoes I wear daily. They are waterproof runners and have been incredible in the unusual high level of snow and slush which has fallen where I live. I also think of all the people in the world that can not even afford shoes, or if they do they are certainly not waterproof, arch supporting, light weight, breathable, cushioned, traction assisted, etc, etc runners.

What things that you can buy are you thankful for? In comparison to the rest of the world how fortunate are you because of this luxury?

Health:

The other thing that I think most of us to be reminded about to be thankful for is our health. This blog is about brain health but I still need to remind myself about my own health, and my family and friends’ health.

When you have a dip in your health and are suffering not too many other things seem more important. You just want to get rid of the pain/suffering and return to a healthy state. I have enough experience with major diseases to empathize with people with current health problems undergoing real suffering (though it is easy to forget). But I laugh at myself when I get a little cold and do not feel well – and immediately, even with this small amount of suffering all I want is it to stop and return to a healthy state. At that stage I am always extremely grateful for my normally good health. I am more clearly aware of how good health is primary to a happy life. And I wonder how people make it through serious diseases, be they acute or even worse – chronic. If you are healthy and not suffering be very very thankful.

Health can be all encompassing, but also can be broken down into smaller compartments. Treasure all of your health -  knees, joints, breathing/lungs, muscle/movement, eyes, etc, etc but also do not forget mental health.  You can have a healthy body but if you have a mental disease it will not matter . The same as a major health issue – say a severely painful arthritic knee can play havoc with your mind – a diverse set of mental diseases will play havoc with the entire system. Not that you can really separate mind and body you need a healthy mind and body to feel ‘healthy’.

The problem of course is that too many of us only worry about their health when they lose some of it. One should take a pro active stance and do all the right things to reduce the chances of lost health. Do the simple things; health eating and exercise. And if you need additional boosters of your health seek them out.

What are you going to do in the new year for your health?

To better brain and body health in 2009.

Dec 23

All the world’s religions, far as I understand, teach us to be kind and giving to your fellow humans – to be altruistic – ‘selfless concern for the welfare of others’. And since the holiday season is upon us (I know this only represent a certain proportion of the world’s religion holiday season) I thought I might tell you a bit of the science behind altruism and one personal story behind it.

One new component to my blog in 2009 will be inspirational stories, but of course there is always the other end of the spectrum that can throw further light on the human condition.

In 1999, taking a year off from pursuing my PhD, I was randomly wandering through a book store looking for inspiration, and was perusing the science section when I randomly came across a book by Andrew Brown: “Darwin Wars: the scientific battle for the soul of man”.

Included in this book was the tragic story of George Price, which is one of the saddest stories I have ever heard. I remember being startled by the story as I read the first few pages standing in the bookstore that day. It lead me to question the PhD I was pursuing and inspired me take a long bus ride to California to talk to two experts in the research field that George Price studied.

Before I tell you George’s story I will briefly outline his background.

- He received his university degree from the University of Chicago with a chemistry degree in 1943, and his PhD in 1946 also from Chicago which included work on the Manhattan project doing uranium analysis.

- 1946-48 he was a chemistry instructor at Harvard, 1950-57 George was a research associate at the University of Minnesota.

- George tried to write a book (57-61), “No Easy Way” (for Harper’s) about the cold war between USA, Russia, and China but he found the world changed faster than he could write about it, so he never finished his project.

- In 1955 he got divorced after 8 years of marriage. Part of the marital problems was that he was a devout atheist equaled by his wife’s deep Christian beliefs.

- While working for IBM (1961-1967) he was treated for thyroid cancer (1966) and during a surgery to remove a tumor there was nerve damage that resulted in his left shoulder  partially paralyzed, and needing to take thyroxine medication.

- With his marriage failing and money from his medical insurance (settlement over the botched surgery) he moved to Britain in 1967 for a fresh start.

London Years:

In one of London’s libraries George Price read the 1964 seminal paper by H. D. Hamilton on kin selection (to complete this sad story see the end of this piece to find out the final chapter in Mr. Hamilton’s life).

Kin selection is when the behavior of an organism is helpful to the reproductive success of its relatives at a cost to itself. This can be viewed as altruistic (altruism), and there is a great deal of research (and controversy) on this subject and the related field of group selection. Humans (and a number of other organisms) display altruistic behaviors, even to non-related individuals. We will help others even if we incur a cost – e.g. run into a burning building to try to save a stranger.

George Price was shocked at the cold formality of the math presented by W. D. Hamilton to explain human kindness to his fellow human. The math placed strict limits on how good humans could be – and whatever goodness there was in humans, there was nothing noble about it – it was simply evolutionary genetics. But it also suggested that humans capacity for lying, cheating, treachery, cruelty,and selfishness was impossible to eliminate – it is part of the evolutionary (human) condition.

So George launched into his own formal examination of altruism without any formal math training. Surprising to himself, he found a even better and more comprehensive mathematical explanation of the evolution of altruism called the covariance equation, later to be called the Price Equation. The equations power gave scientist in the field a formal method to undertake a hierarchical analysis of evolution and natural selection. And of course with this it also allowed the analysis of group selection and altruism. He published his work as a single author 1970 Nature paper (with no references) (He additionally published another Nature paper in 1973).

Even before he got his equation published people realized its potential as illustrated by this story of when in 1968 armed with his equation George went to a cold call visit to Galton Laboratory at University College in which he was directed to Cedric Smith (from James Schwartz, ‘Death of an altruist’):

Smith brought Price to the department chairman. Eighty minutes later, Price had an honorary appointment, an office, and keys. He left walking on air.

Now that is a great story of the recognition of high level ability despite George’s lack of formal training in the field. But unfortunately despite professional success at a more personal level things were not so easy.

It has been suggest that the discovery of his equation for altruism drove George into a deep depression, and then later a search to somehow rescue his lost faith in humanity (the human condition).

In June 6, 1970 George had a deeply religious experience and became a strong believer in Christ (previously he was a strident, dogmatic atheist). With his recently found religion he devoted his life to helping the homeless. He opened his apartment to the homeless to the point he some time had to sleep at his office in Galton laboratory.

Due to new construction he was forced to move from his apartment and no longer could provide shelter for the homeless and he ended up homeless himself. He started living in a number of homeless squats in North London. George was also dealing with his own inner demons that is probably hard for any of us to fully understand. Despite professional success he could not shake his depression.

Christmas 1974:

From the opening of Andrew Brown’s Darwin Wars which stunned me many year ago in which George’s friend W. D. Hamilton comes to his squat near Euston station:

A mattress on the floor, one chair, a table, and several ammunition boxes made the only furniture. Of all the books and furnishing I remembered from our first meeting in his fairly luxurious flat near Oxford Circus there remained some cheap clothes, a two-volume copy of Proust, and his typewriter. A cheap suitcase, and some cardboard boxes contained most of his papers, others were scattered about on ammunition chests.

W. D. Hamilton came to George’s apartment to identify his friend’s body. George was found dead shortly after the Christmas of 1974. Sometime after Christmas George Price cut his throat’s carotid artery with nail scissors. The death of an altruist – was the reality of human nature, and his own equation, which helped formally explain it, too much for George to handle?

Now of course there are many conflicting theories of why George Price took his own life so tragically. He was a devout atheist that discovered a beautiful, but simple, math behind the evolution of altruism. His equation helped explain that humans were not inherently good or bad – but simply a product of evolution. One could not hate the brutality of humans, or rejoice in an act of human kindness. Was it his own cold discovery that first drove him to religion, and then suicide? Like I said he had his own demons – be that simple biologically driven depression (which we still do not understand) or more psychological (assuming you can tease these two apart).

How much more did George Price have inside himself to offer to the world – in the form of greater insight into evolutionary driven human behavior to the good he was doing for the homeless? He supposedly wanted to move into the economic field for he thought his analytical skills could be best utilized there to help humankind.

George Price’s fundamental contribution to the field was largely ignored for the next 20 odd years until S. A Frank (one of the professors I visited in California) reintroduced the field to George’s work (George Price’s contributions to evolutionary genetics). Today you can find many papers that are influenced and inspired by the Price equation.

I am sure I didn’t do full justice to the life of George Price and could only provide a flavor of his story and the story of altruism here in this short blog piece. I encourage those that are interested to read James Schwartz magazine piece, or Andrew Brown’s book to get a more complete picture.

(W. D. Hamilton (considered the greatest evolutionary biologist of the 20th century) died from malaria which he contracted in the Congo as he collected primate feces in an effort to find evidence for the controversial theory of the origin of HIV).

Dec 22

I think some of the biggest breakthroughs for overall health in 2008 occurred in water purification.

Paraphrasing Dean Kamen from the well known Colbert Report video:

“50% of all human diseases in our world today are due to waterborne pathogens…1.1 billion people go to bed each night either thirsty or sick from drinking dirty water.”

There is probably no better way to save more lives in the world other than providing clean water (I will be talking about more traditional high level cellular biology 2008 breakthroughs also in later pieces).

A few years ago the Vestergaard Frandsen Group developed the LifeStraw Personal that is the small and cheap tube that by simply sucking at one end you can get clean water (see LifeStraw wiki). This was mainly developed for 3rd world nations, but it is also used as an emergency water filter by hiker and backpacker types. The filter is rated for up to 700 liters and while it removes 99.9999% of waterborne bacteria but does not remove Giardia lamblia (since it is smaller than 5 micrometers and resist iodine treatment.

However, this year (2008) the company came out with LifeStraw Family that removes 99.9999% of waterborne bacteria, 99.99% of vira and 99.99% of parasites – including Giardia lamblia. Additionally, it is also cheaper (per purified liter) than LifeStraw Personal. At 20 liters of water per day for an average developing nation family the water purifier would provide safe water for 3 years (we will not discuss how much water a family from a develop nation uses each day).

And if you want to see an impressive video of the water purification ability of water by LifeStraw click here.

[youtube]https://www.youtube.com/watch?v=ycEnu9p1GPE[/youtube]

These two products are fantastic and will save countless lives. Now if you thought that it might not be a bad thing to buy personal as part of a survival like package the family version (the best choice) is not available for individual buying (see website) but I have previously seen the personal version availble on the net.

Alternatives small portable versions include:

2008 Backpacker magazine Editor’s choice to MSR hyperflow microfilter.

The HyperFlow filters nasties as small as .2 microns, which removes protozoa (like giardia and cryptosporidium) and bacteria (like E. coli), but not viruses. MSR claims a filter cartridge lifespan of 1,000 liters, and during six months of field-testing we didn’t experience a single slow-down. $99; 7.4 oz; (800) 531-9531; msrgear.com.

You can also check out their miox model which is a similar size to LifeStraw Personal (but note it requires batteries). Another manufacturer of an interesting small water filter provides this solution. Finally, there is miniworks ex.

Clean water for a whole village:

We talked about personal water purification then family but think of the lives saved when you can provide a whole village with clean drinking water.

For an even bigger level of water purification Dean Kamen, the inventor of Segway among other things, announced in 2008 his new invention the Slingshot machine that can provide a whole village with clean water (1,000 liters/day)from any dirty water source including: “ocean, puddle, chemical waste site, hexavalent chrome, arsenic, poison, 50 gallon drum of urine” (as covered in Wired magazine).

How it works is by using waste heat from a Stirling engine electrical generator (which runs on anything that burns – from propane to cow shit, and will beyond providing the heat for the water purification, and obviously will also produce electricity). The whole thing weighs less than 60 pounds, and while the cost of producing the current hand made version is around $ 100,000, with mass production it will only cost 1 to 2 thousand. Think of providing clean water for an entire village for that cost – year after year.

Check out the Colbert Report video of Dean Kamen being interviewed about his invention here.

[youtube]https://www.youtube.com/watch?v=Eqg1Hu0PMG0[/youtube]

Now unfortunately I have read (but couldn’t refind the link) that Mr. Kamen is having trouble getting anybody interested in mass producing this life saving product. Hard to believe but true, here an inventor who is very well known has come up with a life saving invention but still has trouble getting to the next step of mass production. I am hoping some big pocket chartiable foundation like the Bill and Melinda Gates foundation,  which has so much other good work, or others can step in and start the ball rolling.

To clean water in 2009 and millions of saved lives.

Dec 21

While I recently posted my current plans of what I will try to do with this blog in the new year the current year is not over. In the remaining time of 2008 and possibly stretching into early 2009 there are a few things I would like to do.

I will post significant scientific breakthroughs of the 2008 – that I haven’t previously covered. This involves 4-6 pieces – though I am sure I could write more.

Additionally, I am writing a piece about ‘what scientific matter I have changed my mind about over the last year based on recent research’. I think it is always good to make sure you keep an open mind and the ability to change opinion/thoughts based on new research – if the evidence warrants it.

So this might be a could time for you readers to think of anything you have changed your mind about – or that you should change your mind about.

Dec 21

While this blog is only approximately 8 months old, coming close to the year’s end has made me contemplate what direction I will take this blog.

I have mainly been reporting on a wide variety of the latest  research that has an impact on ones brain’s health. For 2009 along with the traditional important research on general brain and body health I will add these:

1: A new fitness routine. This will hopefully provide a new perspective on what is fitness and how to get it. I will be offering a very specific outline of what to do – but trust me many of you will not like it. It can be argued this is a new way of life in general to promote real world fitness and better brain health. I might role this into a separate blog – but I haven’t decided yet. But I would still put out pointers in this blog to pieces in the new blog if I go that route. I may even try to organize a local gathering of people who want to try this new fitness regime.

2: A broad, and hopefully, encompassing theory on human hope, love, energy, creativity, motivation, and decisions (you could say all of this falls under neuroeconomics – but usually things like love and hope doesn’t fall within this field) that will mainly centralize around the dopamine system (but not exclusively). Along with outlining the theory I will also try to explain how this information can be used in our everyday lives to improve it.

3: Inspirational stories and characters. I think by reminding ourselves of various people and situations we might get a better perspective on our own. Hopefully these people and their stories will inspire us to be better, kinder, healthier, and happier individuals – and this section obviously also relates to #2.

4: What is wrong with health/biological science? This will be the most limited amount of blog pieces. But I think this is an important issue. I will attempt to offer some suggestions to improve biological science. This would appear to be the most controversial of my topic matters – but we will see. But I will also try to counter balance this with some positive stories of where advances have been made – and what we might learn from them.

To a great 2009!

Dec 11
Transmission electron micrograph of a myelinat...
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The progressive loss of myelin as we age is now thought to be an important component of brain aging (see here) – so the last thing you want is to take a drug that might interfere with the turnover and remyelination that occurs naturally (though at a reduced level as we age). The new paper I discuss below indicates the widely prescribed drug statin may inhibit myelination – which could have serious consequences for the aging brain.

Statins are prescribed for a large group of patients at risk for cardiovascular disease (CVD) to improve blood lipid profiles – and hopefully lower their chance of CVD. In 2004 it was estimated that more than 25 million people worldwide are taking statins (probably far higher numbers now).

Previously, I wrote a piece  (is long-term statin use bad for your long-term health) suggesting that there could be long term negative consequences of statin use. The post basically described a paper that indicated statins pushed glial progenitor cells into differentiating into oligodendrocytes. The concern is that the faster rate of differentiation of progenitors cells into mature cells may lead to the ‘running out’ of progenitors when we get older.

The new paper by Klopfleisch et. al., 2008 wanted to more directly examine the effect of statins on myelin formation. Interestingly, statins, due to its anti-inflammatory function, has been tested clinically for multiple sclerosis – a progressive demyelinating disease (Volmer et. al., 2004). However, the results presented below raises concern for the use of statins to treat a demeylination disease.

Results:

First the group looked in vitro and found that statins reduced activated p21Ras and its downstream target Erk1/2 by 60-65% in oligodendrocytes. Additionally, Rho-A and ROCK activity was increased by 150-170% (interestingly, these two molecules are also important to axonal regeneration/growth). Previous work had indicated that inhibition of ROCK activity resulted in increased oligodendroglial process formation (indicating a move toward remyelination). Therefore, the increased ROCK activity observed with statin application suggested the possibility of decreased myelination (which the authors were not suspecting).

Now, with their surprising in vitro findings the researchers moved to an in vivo model to test how statins might effect myelination. Mice were fed cuprizone which results in demyelination of the corpus callosum. When you stop feeding the animals cuprizone there is spontaneous remyelination of this same brain region.

Long story made short is the animals that additionally received statins had significantly worse remyelination (both percentage of axons remyelinated and degree of myelination as measured by g-ratio, and measurements of the key components of mature myelin: e.g. myelin basic protein) compared to the control group.

Implications:

While statins improves outcome of animal models of MS called EAE and also has been tested clincally in humans (though not sure on the current clinical use of statins for MS) this paper raises some concerns for the long term use of statins. The author addresses these issue in their discussion suggesting that the anti-inflammatory action of statins may help MS at one level and produce favourable results – but their work still raises a concern of statins negative effect on remyelination.

However, what I am more interested in is that there is growing awareness that the loss of white matter (myelin) which is composed of oligodendrocytes wrapping of axons is an important component of brain aging (review article). If as described in the above paper taking the statin drug result in reduced spontaneous remyelination what would this mean to the aging brain. Throughout life there is spontaneous remyelination as part of a normal turnover and repair process. As we age there is probably more myelin loss and a reduced ability to spontaneously remyelinate. What would be the result of long-term use of the statin drugs you are taking to reduce your cardiovascular risk? Would it be a reduced rate of spontaneous remyelination and hence an overall increase of demyelination – and would this then increase the rate of cognitive decline which is observed with age induced loss of white matter?

It appears we need to take a closer examination of statins effect in brain aging studies (first in animals – though we could investigate deceased human brain samples and compare chronic statin users versus non-users) to get a more complete picture.

Another obvious answer is to make sure you are doing all the things possible that you have control over, such as exercise and healthy eating so you do not fall into the group with serious CVD risk factors and therefore have no need to take statins (or other similiar drugs).

Update: I recently posted about a paper which suggest that statin use reduces the risk of dying (from all causes of death).

Update II: maybe statins do not decrease mortality

Dec 10
myocardial infarction - Myokardinfarkt - scheme
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Intermittent fasting dramatically improves survival rate in an animal heart attack model.

Dietary restriction, in its various forms (the two main forms are a 30-40% reduction in calories called calorie restriciton (CR), and every-other-day fasting (EODF)), increases lifespan in a wide array of organisms (we have known this since the 1920s). More recently, researchers have examined the possible use of dietary restriction for various ‘injury’ models.

In the late 80s early 90s Mattson’s group (or here) discovered that one form of dietary restriction, every-other-day fasting (EODF) in which animals consume no calories for 24 hours followed by 24 hours of as much food as they want, if followed for 8 weeks prior to a chemical induced injury of the hippocampus was neuroprotective and resulted in better behavioral recovery. Latter they went on to find that calorie restriction was not neuroprotective but EODF was, in one of their chemically induced brain injuries.

The group went to explore several injury models that included stroke and myocardial infarction (heart attack). However, it is unlikely a large population of humans will adopt EODF prior to an ‘injury’ for the chance of having less damage from various possible injuries.

Only very recently have a few research groups examined the use of EODF started after an injury. Research that I recently published (Plunet et. al., 2008) reported that EODF started after a partial cervical spinal cord injury reduced lesion size, increased plasticity of the corticospinal tract and improved functional recovery on three different behavioral measurements. Davis et. al., 2008 additionally found that 1 day of fasting reduced lesion size and resulted in better functional recovery after a traumatic brain injury.

But the most dramatic results yet came from a paper that became available yesterday.

Katare et. al., 2008 examined the use of every other day fasting started 2 weeks after permanent occlusion of the left coronary artery – this is a model of chronic myocardial ischemia.

The two leading causes of death in humans (in developed countries) are cancer and heart failure (and think of what will happen with our current obesity epidemic). The 5 year survival rate for heart failure is only 50%, which is similar to some cancers.

Katare et. al., induced myocardial infarction by permanently ligating the left coronary artery of male Wistar rats. The sad truth is that 47% of the animals die within 24 hours. For all the animals that survived to two weeks they were divided into two groups – one group was fed normally (control group), the 2nd group was given food every other second day and hence went through a 24 hour fasting period every 2nd day.

Results:

The degree of heart hypertrophy was reduced in the EODF animals compared to the control group. The amount of fibrosis (scarring) along the border area of the myocardium was reduced in the EODF group. More importanlty, heart function (cardiac volume and LV systolic function) was significantly improved in the EODF group compared to the control fed group .

The group also measured vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and hypoxia inducible factor 1 alpha (HIF-1-alpha) and reported an increase in the EODF group compared to controls, along with increased capillary and arteriole density (as you would expect with an increase in VEGF and HIF-1-alpha).

But all of this might seem boring, or at least pale to the result that most of us would care about if we have a heart failure – which is survival.

Heart failure survival rate:

The survival rate at 100 days post hear failure was 23% for the control group and an astonishingly 88.5% for the every other day fasting group – a highly significant difference. Nearly 4 times greater survival rate (3.847 times to be exact). Just check out the graft.

Just ask yourself which group would you like to be in?

The major weakness of this study was they used relatively young animals and I would hope they will try the same experiment in an age range that would approximate middle age in humans.

Take home:

Now if these results can be replicated – and tested in other organism that might be closer to the human situation (e.g. pig) (and in more appropriately aged animals) this could be an easy to implement and safe treatment (reduced complications compared to many other potential treatments – not to mention EODF in general extends the lifespan of healthy animals) that could save millions of lives.

Note: the dietary restriction form of every-other day fasting was not started prior to the induced heart failure, or even right after heart failure – but two weeks after the heart failure occurred and there still was a dramatic increase of survival rate.

Dec 9

The title of this post seems to be an age old question that is suppose to test your general optimism. The optimist among us views the glass as half full, while the pessimist see it as half empty. Do you think you will be successful or do you think things will be difficult for you? Do you think the current bad economy is going to turn around quickly or are we going to have a serious recession/depression?

(This post can be taken in fuller context by also reading yesterdays post on the difference in imagining yourself currently or in the future.)

Interestingly, overall humans are an upbeat optimistic organism and this attitude probably makes it easier for us to get through tough times (sounds like hope – see this blog piece on the neuroscience of hope). But there can also be over optimism. Overly optimistic thoughts of the future might play an important role in the various economic bubbles we have experienced in the past (Dutch tulip fever), and more  recent times (2001 dot.com bubble, 2007/8 housing/stock bubble).

However, there are many benefits to having an optimist attitude (e.g. you think you will own a house in the future) that includes living a longer life, less likely to have a heart attack or drinking problem (according to this short preview to the paper I discuss below – Schacter and Addis, Nature Neuroscience, 2007.

Research Paper:

Sharot et. al., Nature, 2007 wanted to examine what regions in the brain may underlie individual differences in optimism levels.

The subjects were asked to imagine past or simulate future events such as a break up of a relationship or winning an award while having their brains scanned (MRI). The subjects also scored the imagined event (past or future) as negative, neutral, or positive. After the scans were done the subjects where then asked to give further ratings such as how vivid and strong the imagined event were.

Later all subjects also undertook a test to determine their level of optimism, which included similar questions to the ones I asked at the beginning of this post.

Results:

In general subjects felt that positive future events were closer in time than negative events (which again suggest an optimistic bias). Additionally, the subjects judged future positive events more positive than past positive events (this somewhat surprised me – since the past is real where the future is just a hope. But the past has already been experienced so does not have that novelty/hopeful factor). Both of the above two observations were greater in the more optimistic subjects, as you would expect.

Optimistic individuals had greater activation of the rostral anterior cingulate cortex (rACC) (the exact same brain area discussed in my post from yesterday) when imaging positive future events compared to negative future events than non-optimistic subjects. Additionally, overall when subjects imagined future positive events there was a great correlation between rACC and amygdala (important for emotional processing) activation than when subjects imagined future negative events. This would account for the general higher vividness and strength of future positive events compared to negative future events since the amygdala activation would add greater ‘emotional’ value to the imagination/experience.

Among all the conditions the future negative event produced the least amount of amygdala and rACC activation compared to the other three (past positive events, past negative, future positive). This would suggest we tend not to ‘see/feel’ the potential negative future possibilities (less emotions evoked) and hence are overall optimistic about the future because we can’t see/feel the negative (or we choose not to see the negative).

But returning to the optimistic individuals – they had greater activation of the rACC (and greater correlation between rACC and the amygdala) than the less optimistic individuals. These results make sense when we think of other wider perspective research.

Depressed subjects display reduced metabolism and volume of the rACC region. And as you can imagine depressed subjects have less optimism than the non-depressed individuals (in fact among the deeply depressed many can not, or do not want to, think of the future – because things are so bleak to them. I am sure you could even suggest that part of deep depression/suicide is total loss of hope).

Comparison between future thinking and optimism:

Now do these results of the role of rACC activation in optimism make us rethink the results I presented yesterday (longevity and future thinking) which suggested that rACC activation (when thinking of you now vs future) plays a role in future discounting (the subjects with the largest future discounting had higher activation of rACC in the now vs future comparison (meaning less activation of rACC in the future imagination of themselves – which the authors concluded meant these subjets thought of their future self as a stranger).

Is it possible that the subjects who had less rACC activation when thinking of themselves in the future were just less optimistic about their future? And it would make sense if you are less optimistic about your future self then you would place less value on future events – and hence you would discount the future at a greater rate since you don’t think it will turn out well. Therefore, it would make sense that you would take the 10 dollars now than the 15 dollars in a month.

However, as pointed out in this preview article of Sharot’s paper too much optimism is also not a good thing. If you are overly optimistic about the future then maybe you would not take appropriate safety measures (such as in our ancient ancestor’s time having a cache of food, or in our current world money saved up). One could argue a large contributor to our current financial crisis is the vast majority of individuals in the developed world were too optimistic about the future (they drank – overdosed on – the koolaid). They wore the rose tinted (or should I say the green tinted) glasses that colored their view of the world, of the future and they did not see the reality of the situation. Hence, took on overly optimistic debt load (personal level) or overly leveraged their position (banking/financial sector).

I would guess like most other things in biology we are talking about an inverted U curve – and too little or too much optimism is a problem. The trick is to have the appropriate level of optimism for the current environmental conditions (and be willing to change if the environment changes on you).

Can society at large have an overall change in optimism levels that might play a role in stagnation at one extreme or economic bubbles at the other? What could be possible biological explanations behind this?

Can we separate the role of rACC in both optimism and future discounting (with optimistic individuals have less discounting (at least in most cases until maybe they become too optimistic) – are we talking the same thing in both cases or could under appropriate experimental setting differentiate between optimism and reduced hyperbolic future discounting?

Good science, or at least interesting science results in more intriguing questions.

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