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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).

Feb 24
RAAS Schematic
Image via Wikipedia

It seems every few weeks there is a new scientific paper reporting the benefits of resveratrol or resveratrol-like drugs (e.g SRT1720), which is believed to mediate its effect through SIRT1 (there was a new SIRT1 paper last week in the prestigious science journal - though I didn’t think it was that important). And the popular press are quick to cover every new resveratrol paper.

But I need to remind the readers that while resveratrol was demonstrated to improve life span of mice on a high fat unhealthy diet (Baur et. a., 2006), when tested on mice on a normal diet resveratrol did not extend life span (Pearson et. al., 2008) (also see my coverage of this paper here). However, in the second study the mice did not start taking resveratrol until 12 months of life (middle age) so it is an open question if it would work if started earlier. Though, there are several companies that have a vested interest in reporting positive life span effects, and in theory they have been running the experiments since before 2006 so I wonder why we have not seen positive results published (see here)?

While, there is another clinically approved drug for hypertension that targets the renin-angotensin system (RAS) has now been shown twice to extend the life span of mice.The RAS is involved in blood pressure, water balance, and therefore influences the cardiovascular system. This system releases angiotensin which gets converted into angiotensin II (Ang II) which mediates its effect by acting on the Ang II type 1 receptor. I first became aware of this field of research in a 2009 paper that targeted this system genetically.

Genetic manipulation led to increased life span:

Benigni et. al., 2009 manipulated the RAS by disrupting one of the receptors for Ang II (Atgr1a receptor). The mice with this receptor knocked out had less vascular and cardiac age induced damage. Additionally, in the kidneys more mitochondria were observed as well as an increase in NAMPT and SIRT3. But most importantly the animals with the disrupted Atgr1a receptor lived on average 26% longer.

The researchers give evidence that the manipulation was not simply a result of calorie restriction (well known to increase life span) as both groups weighed the same and consumed the same amount of food.

Clinically used drugs for the RAS also increases life span:

More interesting is that Ang II receptor antagonistic drugs (e.g. Losartan, Valsartan, Irbesartan) which are already use in humans to help with hypertension and cardiac failure (Remuzzi et. al., 2002) also appears to increase life span (as well if they targeted the RAS system earlier in the pathway - see below).

Basso et. al., 2007 tested an ACE inhibitor enalapril (an Angiotensin Converting Enzyme inhibitor) and losartan, which blocks (antagonist) the Ang II receptor (angiotensin II receptor antagonist). They tested these two approaches to inhibit the RAS in rats on a normal chow diet. The animals that were in the treated group started receiving one of the two drugs starting at the time of weaning.

Consistent with the previous paper both groups that were given drugs to block the RAS lived statistically longer; the losartan group lived 19.3% longer and the enalapril group lived 21.4% longer than the control group. In this case the enalapril group did weigh less that the controls, however the losartan group weighed the same as the controls.

And as you would expect with inhibiting the RAS the treated groups also had healthier cardiovascular system in their old age.

What I found interesting even though I try to ready all longevity papers somehow I had missed this RAS story, which looks quite intriguing. On the other hand I am constantly bombarded by the resveratrol story.

Take home message:

Drugs that are fairly widely prescribed (ACE inhibitors, and Ang II receptor antagonists) appears to extend the life span of rats by roughly 20%, even when fed a normal diet. This is further corroborated by genetic manipulation of the RAS via knocking out a Ang II type 1 receptor.

On the other hand we have the reseveratrol drug(s) we always hear about in the high profile scientific journals and popular press and to date they are only reported to increase life span in high fat fed obese mice (the animals taking resveratrol did not become obese despite the diet), with no effects on animals fed a normal diet.

However, we do not know if inhibiting the RAS would improve life span if the ‘treatment’ started at a more reasonable real world  time frame - say what would equate to a 25-30 year old human.

I wonder if we will start hearing about an underground movement of people taking ACE inhibitors or something like losartan, an angiotensin II receptor antagonist?

Now you might say we could just look at all the people that have taken these drugs over the years and retrospectively see if they extend the human life span - however you must remember the people currently taking them already have an underlying cardiovascular problem. In this case we might not see any positive effects compared to the ‘normal’ population without any  cardiovascular complications. Until ‘healthy’ people start taking them - which I am not recommending - we will not know the answer.

Additionally, I will warn you that both ACE inhibitors and angiotensin II receptor antagonists (e.g. lorsartan) like almost all drugs have reported adverse effects. However, it appears that the adverse effects of angiotensin II receptor antagonist seem relatively minor - but for any drug you must take serious caution and technically under the supervision of a licensed doctor.

Feb 13

Update I: maybe statins do not decrease mortality

Today, I will briefly discuss two papers that report reduced mortality by either following the Mediterranean diet, or taking statins.

I wrote a piece early this week about how a Mediterranean diet decreases the chances of the elderly developing mild dementia and Alzheimer’s disease (and an earlier post on how dietary restriction improves memory performance in the elderly). Now I will give the summary of a paper that examine the effects of the Mediterranean diet on all causes of mortality.

Mediterranean diet:

Sofi et. al., 2008 (complete paper freely available here) did a meta-analysis of 12 paper that covered over 500,000 people and found that a two point difference (scores ranged from 0 to 7-9) in adherence to the diet was associated with reduced risk of mortality. They also found that those having that more strictly followed the diet had lower risk of mortality from cardiovascular disease, cancer along with reduced incidences of Alzheimer’s and Parkinson’s disease.

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.

But you might ask yourself the pertient question - what the heck is a two point difference in adherence scale mean?

Adherence to a Mediterranean diet was defined
through scores that estimated the conformity of the
dietary pattern of the studied population with the
traditional Mediterranean dietary pattern. Values of
zero or one were assigned to each dietary component
by using as cut offs the overall sex specific medians
among the study participants. Specifically, people
whose consumption of components considered to be
part of a Mediterranean diet (vegetables, fruits,
legumes, cereals, fish, and a moderate intake of red
wine during meals) was above the median consumption
of the population were assigned a value of one,
whereas a value of zero was given to those with
consumptions below the median. By contrast, people
whose consumption of components presumed not to
form part of a Mediterranean diet (red and processed
meats, dairy products) was above the median consumption
of the population had a value of zero
assigned, and the others had a value of one.

Okay, does that make sense? Are you above or below the median for these categories and who are we comparing ourselves against?

Statins:

Shalev et. al., 2009 examined over 200,000 patients taking statins that included one group that had coronary heart disease, but a second group that had no indication of cardiovascular disease. Those subjects that had > 90% adherence to taking their statin medication had a 45% reduction in risk of death compared to those with < 10 % adherence. And this result held up for both groups - meaning that taking statins also reduced or risk of dying even if you didn’t have any indications of cardiovascular disease.

A stronger risk reduction was calculated among patients with high baseline low-density lipoprotein cholesterol level and patients initially treated with high-efficacy statins. CONCLUSIONS: Better continuity of statin treatment provided an ongoing reduction in mortality among patients with and without a known history of CHD. The observed benefits from statins were greater than expected from randomized clinical trials.

Like the Mediterranean diet reported meta-analysis the statin results do not come from a randomized clinical trial - however they are both interesting. I haven’t yet acquired the full statin paper but would like to see the further breakdown of the data - are the patients that are less likely to adhere to taking their medication just less interested in their health in general - but maybe the same could be said about those that do not adhere to the Mediterranean diet.

And the futurepunduit sums it up well:

If you have high cholesterol do something to lower it. Take statins if you can’t be bothered to radically change your diet. Or take statins and radically change your diet. Or at least change your diet. On the other hand, if you have a death wish I don’t have any arguments to offer for why to take statins. But maybe if you changed your diet for the better you might feel better and less inclined to die.

But I would wonder if we should diet or consider taking statins even if you don’t have high cholesterol since these two paper suggest they both will lower your risk of dying  - though I would do more research before deciding to take statins - there is still ongoing controversy regarding the long term safety of statin use - see my articles here, and here).

Update: maybe statins do not decrease mortality.

Oct 27

In this case I don’t mean stop living life to its fullest – soaking it all up – but rather the possibility of ceasing your ability to smell to increase your life span (hopefully you can continue living life to its fullest without the ability to smell – open question).

Now one problem with almost all longevity papers is the question: will it work in humans? And the human question is actually a two step problem: 1) are the same longevity pathways we observe in lower organism similar in humans (see Ouroboros piece on the IGF-1 pathway), 2) are we ever going to really be able to test intervention ‘X’ in humans (be it calorie restriction (CR) , every-other-day fasting, resveratrol, etc.), because of the length and cost of the study.

I will propose that the olfaction/longevity results of a new paper (and the previous papers reporting similar results) unlike many of the other life extension intervention could ‘easily’ be tested in human in a relatively short time – but first I will discuss the new findings and a bit of the background.

New October 2008 Olfaction - longevity paper

A new paper (Collins et. al., PLOS Genetics, 2008) (freely available) adds to the growing story (at least in lower organism) of how smell (chemosensory) plays a large role in determining life span. They found an anticonvulsant drug (ethosuximide) approved for human use, which had previously reported (by the same group) to extends mean lifespan of C. elegans (by 17%) (Evason et. al., Science 2005) (Evason et al., also found that trimethadione, another human approved anticonvulsant drug – though rarely used due to side effects, extended mean life span by 47%), works via blocking the chemosensory system (which for argument sake I am calling the olfactory system). The group did a fairly exhaustive set of studies which I won’t go into all the details. However, it appears ethosuximide ability to increase this organisms lifespan is mediated via blocking the chemosensory-olfaction system.

Does ethosuzimide block olfaction in humans:

I wonder if there are human thinking about attaining ethosuzimide to test on themselves for longevity purpose. Not necessarily the smartest thing to do. But one question I am sure longevity researchers are wondering is could this drug also extend the lifespan of humans. Well, I would argue there is a simple test they could run tomorrow to give them at least a hint: does ethosuzimide also block the ability to smell in humans. Interestingly, one side effect mentioned for ethosuzimide is the potential loss of taste (but this was included in a host of not so great common side effects). Loss of taste is obviously fairly closely related to loss of smell and I wonder if the loss of olfaction has just gone largely unreported. Interesting possibility at least.

(side note calorie restriction (CR) (at times also called dietary restriction) has also been shown to reduce seizures in animals models (Bough et. al., 2003) and fasting was the inspiration for the testing of a ketogenic diet (KD) (1921) on seizures, and KD is now used for refractory epilepsy in children, and also shown to be effective in adults – though adults find it difficult to stay on the ketogenic diet (Stafstrom et. al., 2003). Overall, a ketogenic diet is argued to be as effective as any current pharmaceutical treatment for children with seizures.

Background:

The first paper I am aware of that directly examined olfaction link with longevity is (Alcedo and Kenyon, Neuron, 2004). The researchers found that taking out specific gustatory or olfactory neurons can extend life span in C. elegans. Taking out (via laser ablation) of a very specific subset of olfactory neurons (AWA) extended life span, while removal of a different set of olfactory neurons (AWC) had no effect. However, taking out both the AWA and AWC together further extended the life span. Interestingly, after further testing they concluded that the olfactory AWA- organisms (or the AWA- and AWC-, or the AWA-, AWC-, ASI- (see below)) that lived longer ate as much as there wild type controls – hence they were not calorie restricted. They next found that a null mutation in odr-7, which is a nuclear hormone receptor that is required specifically for AWA function, lived longer than wild type.

However, the researchers had to remove the AWA and AWC olfactory neurons, along with the ASI gustatory neurons to produce the same longevity extension as is observed with CR. This would suggest that olfaction is not the entire story of CR.

Then one question would would the exposure to food odours reduce the life extension effects of CR?

Drosophila melanogaster

Image via Wikipedia

When fruit flies (Drosophila melanogaster) on calorie restriction (CR) were exposed to food odorants the CR longevity effect was reduced 6 – 18% (Libert et al., 2007) (compared to the approx. 32% increase in lifespan with CR). Therefore, approxmatley 1/5 to 1/2 of the longevity effect of CR was lost with the simple exposure of the smell of food. Exposure of food odorants had no effect on life span in fully fed organisms.

To further explore the role of olfaction the researchers used a loss of function mutation in a specific odorant receptor (Or83b) (functional mutation form called Or83b2) and found organisms with this mutation had a 56% increase in median life span in fully fed females (less, but still significant affect in male fruit flies). So while the animal consumed the same amount of food their inability to smell via the Or83b2 mutation extended their lifespan. A ‘rescue’ experiment that involved the expression of the ‘normal’ version of the Or83b transgene resulted in normal life span (a loss of the increased life span).

They next tested the Or83b2 functional mutation on a variety of CR diets. All mutated Or83b2 groups lived longer than the controls over the various CR diets. But interestingly CR further increased the already dramatic increase in median life span of the Or83b2. (I had forgotten about this particular result from this paper – which has implications – see below. ). These result again (along with the above mentioned data) suggest that while olfaction plays an important role in CR’s life extension effect but it is not the sole mechanism.

(side note: the smell of food in humans is reported to increase insulin levels - which could drive the insulin-IGF-1 pathway (for review see Brand et. al., 1982))

Summary:

Now there are several papers (I did not mention them all here in this piece) that indicate the importance of smell, and not just food consumption on longevity – at least in lower organism. The question then becomes is this also true in higher organism, and most importantly to us egocentric humans, does it work in us (which is also true for all the potential longevity interventions even if they have been observed hundreds of times in multiple organism as seen with dietary restriction)?

Olfaction in humans and longevity – we can test this.

While I started out this piece pointing out the length and difficulty of ever testing the longevity effects of the various potential interventions. However, in regards to the olfaction effect on human longevity we should be able to ‘quickly’ and easily find out the answer. No we are not going to ask humans to come into the laboratory late one night and excise their olfactory system. There is already a group of humans that are unable to smell.

Anosmics are unable to smell. There are congenital anosmics and non-congenital (via accident, or infection of the olfactory system, etc). According to the numbers there are approximately 2 million anosmics in America. I do not know the number of congenital anosmics (some preliminary data suggest around 30%).

What I am proposing is select out a large sample of anosmics that have no memory of every having the ability to smell (hence they at least have not been able to smell since the age of 4 to 5) and look at their life span compared to appropriately matched control group. Simple enough. There would be a wide range of ages including people close to the end of their lives, and we could possibly use data from those that are already deceased if we have clear enough evidence of when they lost (congenital or viral) their olfactory ability to speed up finding out the results. (I will volunteer to be part of the anosmic group since I have never had the ability to smell).

This way we can bypass 10 or 20 years of animal research on organisms above C elegans and fruit flies, and jump to the front of the line and see if knocking out olfaction in humans enable them to live longer.

(Another interesting question, but obviously more difficult to test, would be does the combination of olfaction KO and some form of dietary restriction cause a further increase in human life span?)

However - maybe we really want to smell the roses:

This won’t address the question of will humans willing choose to forgo olfaction for the chance to live longer (same can be said regarding dietary restriction other than we already know a vast majority of people would not choose this option – hence why it would be so lucrative for whatever company comes up with a CR mimicker).

I guess the questions is would you forgo the ability to smell the roses to live a longer life (assuming taking out human olfaction increases life span) ?