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Mar 31

Several weeks ago I wrote a piece that reported on a paper (Shalev et al., 2009) that indicated that those patients that adhered to their prescribed statins had a decreased mortality rate compared to those that did not adhere.

However, I would be doing a disservice if I didn’t report the excellent critique of this paper by Michael R. Eades on his blog.

The problem with the statin study, as Dr. Eades points out, is the separation of those that self-adhered to taking the drug and those that didn’t adhere. Because maybe the type of people that don’t adhere to their prescription are fundamentally different that those that do adhere. One possibility is that those adhere to their medication care more about their health.

Dr Eades talks about a near 30 year old New England Journal of Medicine study and points out these interesting results of this pre-statin drug used to lower cholesterol:

Subjects were randomized into two groups - those in one group got the drug, those in the other got the placebo.  After the subjects were on either the drug or the placebo for five years, researchers calculated the mortality from the number of deaths in each group.  Turned out that the five-year mortality of those on clofibrate was 20.0 percent whereas the five-year mortality of those on the placebo was 20.9 percent, or essentially the same.  Taking the drug was no different than taking the placebo, i.e., the drug was worthless. Had one of the researchers not looked a little closer, that would have been the end of the story.

When the data were looked at from the perspective of how many people actually took the drug as prescribed, the researcher discovered that those subjects who took at least 80 percent or more of their clofibrate had a five year mortality of only 15.0 percent, substantially less than the overall five-year mortality.  Those who took their clofibrate sporadically had a five-year mortality of 24.6 percent, significantly higher than those who took it as directed, a piece of data that would seem to confirm the efficacy of clofibrate.  Right?  Not necessarily.  Let’s look at compliance with the placebo.

Turns out that those subjects on the placebo who regularly took their placebo had a five-year mortality of 15.1 percent while those who took their placebo sporadically had a five-year mortality of 28.3 percent.  What this study really showed was that there is something intrinsic to people who religiously take their medicine that makes them live longer.

You should read his complete piece, but I think you get the general story. The bottom line is it didn’t matter if you were taking the medication or the placebo you lived longer if you were the type of person that would adhere to taking your ‘medication’. And among those that regularly took their medication there were no difference between those that received the cholesterol lowering drug or the placebo.

Dr. Eades goes on to point out another paper published in Lancet that found very similar results (Granger et al., 2005). In this case they were looking at congestive heart failure comparing a drug and placebo.

Those taking the drug (Candesartan) showed no difference in mortality compared to those taking placebo.  But when compliance was evaluated, those taking either the drug or the placebo as directed had much lower mortality than those taking either one sporadically.

Going back to the 2009 cholesterol lowering statin drug study the reported decrease in mortality is in the group that regularly took their medication compared to those that didn’t bother to take their medication regularly. And now you know from the 30 year old study this type of measurement (study) is not very valid.

Dr. Eades piece goes on to dive into further details such as all the actual randomized double blind clinical studies while reducing cardiovascular death in those with increased LDL levels, do not show any reduction in overall mortality (he argues there is an actual increase in cancer and other causes of death that balances out the gains in the cardiovascular system).

He concludes (but read the whole piece):

Don’t fall for the false promise of this or any other version of an observational study.  These kinds of studies do not prove causality.  Nor do they prove that a drug regimen works.  The patients in this study who religiously took their statins had better all-cause mortality than those who didn’t.  But, as we saw above, adherers always have better all-cause mortality than non-adherers.  In this case, was it that the adherers lived longer or was it that statins conferred some sort of benefit.  We can’t tell.  But we do know that in the real studies, the randomized control trials, statins didn’t do squat, so my vote would be that what we’re seeing here is an adherer effect and not a statin effect.

I am not saying I agree with all the views and opinions of Dr. Eades, but I think his argument regarding the above discussion is valid.

see also:

statins bad for myelination?

long term statin use bad for your long term health?

(Dr. Eades also correctly points out how it is impossible (or nearly impossible) to run a correct randomized double blind studies with many lifestyle interventions - such as the exercise study I discussed yesterday - and hence you can not ‘prove’ anything with these type of interventions).

Mar 30

Yes, you should exercise if you want to be healthier and live longer. This blog piece is an example of me (and others) telling the same story over and over again in the hope of people changing their behavior.

Some of the readers of this blog are interested in longevity research and living longer. Well, until there are available clinical treatments out there you really have no excuse for not exercising.

A new paper finds a nice relationship between exercise and living longer.

Byberg et al., 2009 followed 2,205 men starting at the age of 50 (starting 1970-73) and followed them for the next 35 years.

For activity level they broke it up into 4 categories (initially):

1 Do you spend most of your time reading,
watching TV, going to the cinema, or engaging in
other, mostly sedentary activities?
2 Do you often go walking or cycling for pleasure?
3 Do you engage in any active recreational sports
or heavy gardening at least 3 hours every week?
4 Do you regularly engage in hard physical training
or competitive sport?

Since only 5% of the subjects fit into category 4 (the most active) so they designated group 1 as low activity, 2 as medium, and those in 3 and 4 as high. Now I am not sure what people consider ‘heavy’ gardening or if they should fall under high activity but the results speak for themselves.

The raw numbers are: for low active group the absolute mortality rate was 27.1 per 1000 person years, for the medium active group 23.6, and the most active group (# 3 and 4 from above) only 18.4 . Hence, the most active group had a 32% reduction in mortality compared to the low activity group, and 22% better than the medium active group. When you convert this into years, the highly active individuals were expected to live 3.8 years longer than the least active group, and 1.8 years longer than the medium group.

Now while some of the important variables were controlled for (e.g. BMI, blood pressure, cholesterol levels) but this was not true for all of them with smoking being the most obvious (low active group 60.9%, medium active group 53.0%, high active group 46.5%). However, the researchers point out they take all this into account:

Our analyses also took
into account changes over time in potential confounders
including smoking, obesity, self perceived health,
and morbidity and in classic risk factors for mortality
including hypertension and total cholesterol concentration.
We also adjusted our estimates for socioeconomic
group and educational level.

After they do all the adjustments for these different starting points the most active group still live 2.3 years longer than the low active group, and 1.1 years more than the medium active group.

The authors point out in their discussion section that these are similar to previous results:

Time dependent life table analysis for estimation of remaining
life expectancy among 50 year old men in the
Framingham Heart Study showed 3.9-4.1 years longer
life expectancy for men reporting high physical activity
and 1.6-1.8 years longer life expectancy for men
reporting medium physical activity
, compared with
the sedentary group.13 14 We obtained estimates of
similar magnitude.

(#13 Franco et al., 2005, #14 Jonker et al., 2006)

However, these results just further add to the accumulated knowledge (and common sense) that more or less life long exercise will reduce mortality. But the researchers were more interested in what would be the results on changing amount of exercise starting somewhere between 50 and 60 years of age.

Now this is where things get interesting. Obviously, the best group to be in was the still highly active group.

The formerly highly active group that changed to either low or medium activity level were now the same as the low or medium active group. This suggest that the trick is to keep moving - keep being highly active past the age of 50 if you want your best chance of living a longer life.

Most interesting was the group that tried to change from low or medium activity to high activity. There was an actual increase in morality in those that changed to for the low/medium to high activity for a number of years.

The authors say this:

During the first five years of follow-up, however, the mortality rate was 2.6 times higher in men who had increased their level of physical activity compared with men whose physical activity was high but unchanged (table 3).

We studied men who increased their physical
activity level in more detail. The mortality rate after
more than 10 years of follow-up was halved in men who
had increased their physical activity to a high level both
from a medium (adjusted hazard ratio 0.58, 0.39 to
0.87) and a low (0.51, 0.26 to 0.97) level. There was no
evident reduction in mortality rate among men who
increased their physical activity from low to medium
(0.81, 0.51 to 1.31).

Now to me the negative trend looks longer than 5 years to me, but maybe this is reflected by subjects who change to heavy exercise at the age of 60. However, the authors try to clearly state their results in the conclusion:

Increased levels of physical activity in middle age have
an effect on mortality. After a 10 year period of
increased physical activity the excess mortality seen in
inactive men was reduced to the same levels of
mortality as seen in physically active men. There is,
however, a period of at least 5 years before this risk
reduction during which the risk is higher. The halved
mortality rate after 10 years of follow-up after increased
physical activity between the ages of 50 and 60
(compared with continued inactivity) was similar to
that seen after smoking cessation (compared with
continued smoking).

They mention previous work that stopping smoking results in a 40% lower mortality rate (after more than 10 years of follow-up), which they argue is similar to what they are reporting for the starting of heavy exercise in middle age. For comparison purpose the authors contrast exercise with other medical interventions:

The effect we observed after increased
physical activity, however, is larger than the effect of
a 1 mmol/l reduction in cholesterol concentration(18%
reduction of total mortality)41 and the effect of
treatment with any antihypertensive drug (10% reduction
of total mortality).42

Now my thinking of why the researchers observed an increase in mortality in those changing to high activity level after the age of 50 is that the ones that do decide to change at this point in their life (and not earlier) are the ones at most risk. Either they have pre-existing health issues, or have received a health scare and out of fear change into an active lifestyle. However, for some of these subjects their unhealthy system can handle this level of exercise and they end up dying. But this is my supposition.

Problems with study:

Observational studies like this one can not control for all the variables. It is possible that those subjects that started heavy activity also changed other life style choices such as a healthy diet and/or more regular visits to the doctor. With this and more in mind I will write a follow-up to how statins may results in a reduction in mortality, indicating things are always as straight forward as reported.

Bottom line:

Taking the results at face value:

If you want your best chance of living a long healthy life exercise throughout your life - don’t just stop and dramatically reduce your exercise level after the age of 50 (or you lose the benefits).

If you are 50 or older and have finally decided to change make sure you see your doctor to make sure you are healthy enough for exercise - but overall the results from the above paper indicates you will gain (on average) if you start at 50+. I would consider slowly building up your tolerance to exercise and your increased activity level.

The effect of staring exercise after the age of 50 is similar to what is observed with stop smoking (which is quite substantial).

And even if exercise doesn’t allow you to live a couple extra years - you will be able to enjoy more life in the years you have. Keep moving, keep enjoying life.

see also: keep moving for greater health and longevity.

Mar 26

Our modern world is complex and constantly changing - do you have the ability to change your behavior in our ever faster changing world?

We all make mistakes, the question is can you learn from your mistakes. At the gene level can a polymorphism of a gene affect our ability to learn when things change? Sometimes in life a tried and true behavioral response stops working - the question is how quickly do you realize that the old way is not working, and you change your behavior to the new reality.

In the labs researchers study the ability of humans to adapt to a changing environment by using a reversal learning task. After the subjects have learned a task by responding to a stimulus in a certain fashion for a reward (on a probabilistic level in the paper under discussion) the researchers suddenly change the rules and what you did previously for reward is no longer rewarded (at a probabilistic level). What do you do? The environment has changed, how long does it take you to learn the changing environment? This is the general basis of reversal learning.

Study:

Jocham et al., 2009 studied the reversal learning ability in 28 subjects young health subjects (20-32). The variable the researchers were wondering about was the dopamine D2 receptor. This receptor in humans has a number of polymorphism, but the particular one being studied is called the A1 allele which is associated with a reduction in the number of receptors in the striatum (approximately 30% reduction).

If the subjects have the A1 allele (less D2 receptor expression) they are designated at A1+

Behavioral results:

The subjects underwent a probabilistic reversal learning task that consisted of a total of 18 reversals - in which the subjects had to realize (learn) the rules had changed and adjust their behavioral choice.

The overall amount of reward obtained by the two groups (A1+ vs A1-) did not differ, nor did the number of reversal errors. However, when analyzing the 8 trials after a final reversal error the percentage of trials in which the subjects maintained the correct response before switching back to the now incorrect response is reported in the figure below.

As you can see from the above the graph the subjects with the A1+ allele were more likely to be incorrect - by switching back to old previous response. Or you could say the A1- subjects were more persistence in maintaining the new found rules. The authors point out the A1+ subjects in general switched back and forth between the two choices compared to the A1- group (what would the A1+ group do with many more choices?).

Imaging of the brain:

When there is a reversal of the rules the subjects are no longer rewarded for their previous response and this is considered negative feedback. Based on the subjects current understanding of the rules they were expecting to be rewarded for their correct response - but if the rules had changed there was no reward and hence negative feedback. The researchers scanned the subjects (fMRI) while doing the reversal learning task.

The graded increase of response to negative feedback observed in the rostral cingulate zone was less in the A1+ group as compared to the the A1- group. Additionally, the A1+ subjects had less left ventral striatum and right lateral orbitofrontal cortex activation.

Authors’ conclusions:

…our results demonstrate that a genetically driven
reduction in striatal D2 receptors affects performance in a probabilistic
reversal learning task. The behavioral alteration did not
consist of increased perseverative errors. Rather, A1+ subjects,
having reduced D2 receptor density compared with A1- subjects,
had difficulty in maintaining the newly rewarded response
after behavioral adaptation in response to a change in task rule
.
Moreover, these subjects were in general more likely to switch
back and forth between the response alternatives
. In particular,
A1+ subjects frequently switched to the other response although
they had just been reinforced for the response they made
. These
subtle behavioral differences were accompanied by changes in
feedback-related BOLD signals.

So what, you might be asking?

Good question. Well maybe you are one of those with the A1+ polymorphism.

Previous research indicate that A1+ subjects have a reduced capacity to learn from negative feedback (Klein et al., 2007), and when combined with the paper under discussion it suggest the D2 receptor may play a role in feedback learning in general.

15-21 % of the north American population (European origin) have the A1+ polymorphism (Kidd et al., 1996). This polymorphisms, which results in a reduction in D2 dopamine receptor, has already been linked with pathological gambling (Comings et al., 1996), addiction (for review see: Foll et al., 2009), and obesity (Stice et al., 2008). All of these three you could say at one level or another is related to reduced ability to learn from negative feedback, or feedback in general.

More so, beyond your genes there are various external factors that decrease or increase your D2 receptor levels.

You can make certain real life choices that increase your D2 expression, or other choices that decrease your D2 levels. If you had a choice which way would you want to go - reduced learning ability or increased ?

Keep coming back and I will tell you the brain hack to increased your D2 receptor expression.

Mar 24
Photograph of acute MCA stroke.
Image via Wikipedia

Earlier I have written about how social isolation can play a general role in overall health (see these two posts: increased social interactions improve health, and social isolation: what happens to the brain). Today I am going to discuss a paper that examined social interaction/isolation and stroke.

Karelina et al., 2009 (PNAS) wanted to examine potential mechanism of social isolation on health, and in this case stroke survival/recovery. The researchers either individually housed the male mice (socially isolated), or pair housed with an ovariectomized female (social housing) starting 2 weeks before the induction of stroke (mice and rats are highly social animals like humans). Next, stroke was induced using the middle cerebral artery occlusion (MCAO) model and the individual or paired housing was continued throughout the rest of the experiment.

Results:

Let us first look at survival, arguably the most important real life outcome (though at times ignored in these type of studies). Only 40% of the individually housed post-stroke mice survived 7 days, but 100% of the pair housed animals survived. Yes, you can say wow! (Side note there was an equally dramatic result of every-other day fasting after an animal model of heart failure).

The differential survival rate caused a problem for the experimenters because it made them wonder if it was correct to compare the lesion size of the few surviving animals from the individually housed group - because the rest had died with the idea they had more ‘damage’, with the paired housing animals (if only comparing the animals surviving to 7 days there were no differences between the two groups in terms of infarct size).

In the next part of the experiment they did the same MCAO injury but examined the animals infarct size (how much brain damage) at both 24 and 72 hours post injury (where survival rate was similar between groups). At both of these time points the grouped housed animals had reduced infarct size compared to the individually housed animals, with the bigger effect at 72 hours compared to 24 hours (see diagram).

Now the researchers wanted to get down to a mechanism for their results with inflammation / immune response being a good bet. They examined a number of cytokines (involved in the immune system), but narrowed in on the finding that interleukin 6 (IL-6) brain protein expression was lower in the individually housed post-stroke animals compared to the socially housed group 24 hours after injury (but the serum IL-6 levels were higher in the individually housed group - see below). When they blocked the increase of IL-6 in the socially housed animals the beneficial effects of social housing was lost (as measured by infarct size) - indicating that IL-6 was playing a meaningful role in the better outcome of the socially housed animals.

A number of others have found that infusions of IL-6 after ischemia is neuroprotecive (e.g. Loddick et al., 1998).

An interesting result of this paper is the opposing level of IL-6 when comparing brain protein levels and blood serum levels. The authors talk about this in their discussion section.

Our data indicate that although central IL-6 is down-regulated (Fig. 3B), peripheral levels of IL-6 protein are up-regulated (Fig. 3C) in isolated relative to socially housed mice. This association between elevated levels of IL-6 and increased infarct size is consistent with
the clinical literature on serum IL-6 concentration and stroke outcome. Within the clinical literature, elevated peripheral IL-6 is a reliable predictor of stroke occurrence, severity, and mortality (33, 34). The relationship between peripheral IL-6 and stroke outcome is indicative of an increased proinflammatory state, largely because of IL-6 mediated signaling of acute phase
protein induction (i.e., CRP) after stroke (15, 35). Thus, contrary to its central actions, peripheral IL-6 is proinflammatory and is therefore a target of ongoing clinical trials for stroke patients (36).

This can be confusing because most of us think of IL-6 as being pro-inflammatory (but in reality it can act as both pro-inflammatory and anti-inflammatory - nobody said biology was simple), but the authors go on to a further explain (CRP = C-reactive protein):

Taken together, an up-regulation of peripheral IL-6, along with low central IL-6 expression, is consistent with an altered inflammatory state that contributes to poorer ischemic outcome in the socially isolated mice. Further, the increase in serum IL-6 among socially isolated mice is consistent with a previous report of increased intraischemic serum CRP concentrations in isolated relative to socially housed mice (8).

Conclusions:

There is already research out there that indicates that social isolation in humans is linked with worse outcome after stroke (Bolden-Albala et al., 2005) (in this case it was pre-stroke isolation - similar to the animal paper under discussion). The paper presented here further reaffirms these clinical results of the benefits of social interaction, and gives a potential mechanism - IL-6 (high brain levels, low blood levels).

Therefore, you would conclude that as a society we might try to intervene by providing stroke victims who do not already have good social support this beneficial treatment. However, in the above animal study the social interaction was started two weeks before the induction of stroke - which obviously we can not control in humans so easily. An interesting question would be does social housing the mice after stroke also work? Another question would be does the housing partner have to be of the opposite sex?

Even if social support is effective if started after the stroke in animals models and society could offer this service as a health service would you get the same results in humans? Would a paid for social support provide the same benefits as ‘genuine’ social interaction - I don’t know. And what about if the person receiving the paid for support realizes that the social support they are receiving is mandated - would it reduce its effectiveness?

I guess what I am asking is can social support work if the person receiving it thinks it is not genuine - and it is provided just to ‘treat’ them? My gut instincts says probably not - but I am open to hear what others think about this matter.

Maybe scientist will have to develop a IL-6 ‘pill’/treatment to bring about the positive benefits of paired housing. Do you think social interaction is only affecting IL-6 and that by giving animals or humans IL-6 that you would get all the same benefits?

(side note: do neurochemical changes brought on by social interaction play any role in the neuroscience behind the effectiveness of alcoholic anonymous I discussed yesterday?)

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