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Feb 26
Pandemic of Lifestyle Diseases
Image by colros via Flickr

We have all been told, and it is widely published that unhealthy eating and obesity is likely accounting for around 30% of cancers (Calle and Kaaks, 2004). The question is then why?

The paper I discuss today is not examining why an unhealthy diet may lead to developing cancer, but rather if what you eat plays a role in the ’spreading’ of cancer, which makes it far more likely to kill you.

A new paper by Le et. al., 2009 in BMC Cancer examined this question by testing animals that had tumors implanted in them on either a high fat diet (34.9% : mouse D12492 diet which equates to 60% fat in caloric terms - according to the company documentation) and a normal chow diet (4.25 % fat: 7001 diet, which equates to approximately 12% of their caloric intake - according to the company data sheet - which is the normal amount of fat typically fed a lab mouse). They then used a fairly new technique (which I discussed briefly about in my recent talk at BIL 2009) which allows the detection of metastasizing cancer cells in the blood stream. As I also discussed in my talk the common thinking is that 90% of cancer death is due to the metastasizing cancer cells. These critical cells are not what most cancer research concentrates on, instead the tend to focus on treatments that reduce the primary tumor and not treatments that reduces the deadly metastasizing cells (in the past this could have been due to technical limitations).

What the researchers found was that the high fat diet resulted in a 300% increase in metastasizing cells detected in the blood stream (at two weeks after cancer implementation - but at 4 weeks there were no differences between the two diet groups - but this is of less importance since enough cells had already escaped into the blood stream). Through the blood stream and lymph system is how these cells migrate to a new organ and wreak their havoc. Interestingly, the primary tumor size was the same in both groups throughout the experiment.

To further corroborate this finding they looked at how many cancer cells had escaped to the lungs. In the high fat fed animals there was a four fold increase of cancerous cells found in the lungs compared to the normally fed animals (at 4 weeks after cancer cell implementation).

This study did not examine if a high fat diet leads to increase incidence of cancer (though the Calle and Kaaks, 2004 report in their review paper that being overweight does increase the incidence of cancers in humans) - but rather if a fatty diet leads to increased cancerous cells metastasizing - which probably ends up killing you.

The researchers next wanted to get into the details of what type of fat is bad, and the role of specific fat deposits we carry on our body.

The researchers found that linoleic acid, which is mostly found in polyunsaturated fat, when added to cancer cells in a dish resulted in increases in binding proteins and morphology which are indicators of a potential for great migration/metastasizing propensity. However, oleic acid, (55 -80% of olive oil) found in monosaturated fats, did not result in these same changes.

Next, they tested if the secreted factors from visceral fat (see a previous piece I wrote on visceral fat and longevity) played a role in cancer cell migration. The found the secreted cytokines from visceral fat (which are different than the cytokines released for subcutaneous fat) attracted cancer cells. And the free fatty acids (FFA) from the visceral fat resulted in the cancer cells having less cell to cell (cell-cell) contact - which would allow them to roam about inside your body and visit other organs.

In summary (from paper):

…imaging reveals intracellular lipid accumulation is induced by excess free fatty acids
(FFAs). Excess FFAs incorporation onto cancer cell membrane induces membrane phase
separation, reduces cell-cell contact, increases surface adhesion, and promotes tissue invasion.
Increased plasma FFAs level and visceral adiposity are associated with early rise in circulating
tumour cells and increased lung metastasis. Furthermore, CARS imaging reveals FFAs-induced lipid accumulation in primary, circulating, and metastasized cancer cells.

Problems with the study:

The high fat diet was ‘extreme’ in the terms of around 60% of the calories consumed by the mice came from fat. It would have been nice to test a more typical western high fat diet consumed by humans (e.g. 25-45% fat with a high percentage of the fat coming from ‘bad’ fat).

The second problem is they used a cancer model in which they implant a tumor underneath the skin compared the more clinically relevant model of putting the tumor in the organ of the tumor origin (I also discussed in my recent talk at BIL).

Simple take home message:

Obviously if you have cancer avoid a high fat polyunsaturated diet so your cancer cells are less likely to spread to other organs. In addition right now today you do not know if you have cancer or not - hence you should still avoid the bad fat diet to reduce the probability of cancerous cells escaping the ‘potential’ primary tumor and invading other organs - not to mention the past research that shows obesity is related to increased incidence of developing cancer.

Make sure you have low levels of visceral fat - meaning exercise and eat healthy.

You might also find my piece of the relatively lack of progress in reducing cancer deaths over the last 55 years interesting, and how researchers are realizing many pathways are involved in cancer.

Feb 25

Would you believe me if I told you only 11% of patients are receiving rigorous scientifically backed evidence based treatment (at least in the case presented below)?

For argument sake let us presuppose that your overall health is half based on you doing the correct things (making healthy lifestyle choices), and half based on your doctor doing the right thing.

It is an open argument if most of us in the developed world who have the opportunity to make the correct lifestyle choices actually choose wisely - but again for argument sake and based on most of the readers of this blog are probably mostly making the wise healthy choices what about the other half of the equation - the doctor choices of the appropriate treatment for you?

According to a recent study (Tricioci et. al., 2009, published in the well respected JAMA journal) reported in the Wall Street Journal regarding heart disease treatment the numbers do not look good. Of the 2,700 heart disease patients only 11% of the patients received treatment supported by high-quality scientific evidence. About 50% of the treatments given had limited scientific backing. From the WSJ article:

The findings from the JAMA study reflect the challenge doctors and patients face in choosing the best course of treatment for a variety of conditions. And they underscore that even though drug and device companies, government agencies and philanthropic groups have spent billions of dollars developing and testing new treatments in recent years, much of what happens in the doctor’s office or the hospital operating suite might not be based on rigorous scientific evidence.

To give you a bit of background of what is, or is not, considered good scientific evidence I quote from the WSJ article.

The American College of Cardiology and the American Heart Association have been jointly issuing guidelines to doctors on care of cardiovascular patients for more than 20 years. Recommendations based on multiple randomized clinical trials, in which patients are randomly assigned a treatment, are considered having the highest level of evidence. A single randomized study or non-randomized studies comprise the second level, while recommendations backed by expert opinion or case studies are considered having the weakest evidence. Guidelines are also ranked by whether empirical evidence or general opinion supports that a treatment is useful and effective or not.

Now I believe it isn’t the case that the doctor is necessarily doing anything wrong - the problem is the lack of adequate clinical trials testing which treatment is actually most effective compared to weaker evidence including such things as ‘expert opinion’. Opinion based on experience is valuable, but it is not science - though sadly in many cases it is the best we have.

However, things may change in the future with the new Obama administration as reported in WSJ.

This month, the Obama administration and Congress budgeted more than $1 billion of the economic stimulus package to fund research for comparing the effectiveness of different treatments in head-to-head studies aimed at providing evidence to clinicians and insurers on the best treatment strategies.

“We need those studies to make the kind of changes in health care that are being talked about — being sure we get the best possible care for our patients in the most cost-effective manner,” says Sidney Smith, a medical guidelines expert and cardiologist at University of North Carolina, Chapel Hill and senior author of the JAMA paper.

Though with the current state of the economy I wonder if this will be possible - I hope so. In most cases the the drive behind most large clinical trials are pharmaceuticals trying to get a new drug approved. From the WSJ article:

One reason for the lack of stronger evidence is that the large “megatrials” that have dominated cardiovascular research in the past decade were sponsored by drug and device companies. While those studies provide an important source of information, they are typically designed primarily to win approval for a treatment or to widen the market for a therapy already on the market, and not to guide treatment decisions, according to the JAMA study.

I am not sure what to say - it appears many times the clinical studies have not been performed and we simply do not know what is the most effective treatment for various health conditions (I will try to ignore the most ‘cost effective’ treatment discussion). Clinical trials are expensive and there are many variables you have to worry about (e.g. individual patients additional complications) and so as a society we might not be able to afford to thoroughly test what is the most effective treatment out of all the options that currently exist. One thing the above research suggest is for the patient do their best to be informed and knowledgeable (though this is not an easy task).

The second thing the above research brings to mind is you might want to pay even more attention to the half of the health equation you have more control over - you making the best daily health choices.

Feb 24
RAAS Schematic
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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 23
  * Description: Coffee cortado (An latte...
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Many of us drink coffee, but worry that we might be harming ourselves. While nothing is carved in stone, there is research that suggest that coffee drinking will reduce suicides and heart disease (but read the whole piece to get the full J curve story).

I was going to blog about a resveratrol alternative to increase your life span today - but with a new paper coming out on coffee I decided that it might be more important, and might do more real world ood (but tune in tomorrow for the resveratrol alternative story).

Cardiovascular / Heart disease and coffee:

The new paper (hat tip to futurepundit) Lopez-Garcia et. al., 2009 followed over 83,000 women over 24 years and studied the risk of stroke in this group. They found that women consuming coffee had a lower risk of stroke. Those that consumed about 1 cup per day had a 12% reduction in risk for stroke, 2-3 cups/day had a 19% reduction, and those that consumed 4 or come cups a day had a 20% reduction.

In men (Kleemola et al., 2000) the highest incidence of heart disease (myocardial infarction) was in those that drank no coffee (study include more than 20,000 age 30-59). Coffee consumption reduced the risk of heart disease - but only in those men who did not smoke. But for those men that smoked high coffee consumption increased risk of heart disease. But we all know that you shouldn’t smoke, but definitely don’t smoke and drink coffee. In general, for men the biggest reduction in heart disease induced death was in the moderate coffee (1-3 cups a day) consumption group (U shape curve). In this study, for women increased consumption of coffee was correlated with reduction in both death by heart disease but also all causes of death  - wow! (the more coffee the better - but see below).

More papers that see the same trends as above: Greenberg et. al., 2008, Wu et. al, 2008.

Note: there is still debate going on about the possible negative acute effect of coffee consumption versus long-term positive effects (Riksen et. al., 2008).

Researchers found similar results with teas (both green and black). Arab et. al., 2009 did a meta-analysis of all the human clinical and observations studies. In total there were data from 194,965 individuals and they found that those that consumed 3 or more cups of tea had a 21% lower risk of stroke.

Coffee consumption and risk of suicide:

Depression is a serious problem (see my piece on the personal and societal cost of depression) that too often leads to the tragedy of suicide.

In a 1996 study (Kawachi et. al., 1996) researchers followed 86,626 registered female nurses (age 34 - 59) over a ten year period. After controlling for several variables they found that those that drank 2-3 cups a day had a a 66% reduction in suicide, and there was a 58% reduction in those that drank 4 or more cups a day (hat tip to drinkingcoffeeallthetime - as she wrote her piece honoring David Foster Wallace and pointing out the reduction of suicide with coffee intake).

Not so quick as we look at the J curve: A sweet spot of coffee consumption.

A followup study (Tanskanen et. al., 2000) looked at things a bit more closely and found you have to be careful at the high end of coffee consumption. They followed over 43,000 subjects (both males and females) for just over an average of 14 years. 2-3 cups a day of coffee correlated with a reduced risk of suicide by around 34%, and 4-5 cups reduced it by around 18%. However, for those that drank 8 or more cups of coffee there was a 58% increase risk of suicide, compared to moderate coffee drinker. Hence, the J curve, a moderate amount of coffee reduces the risk of suicide (bottom of the J - better than the beginning of the J), but too much coffee is the worse scenario - the highest risk of sucide.

Bonus: According to a recent review (Nkondjok 2008, Cancer Letters) overall coffee appears to reduce the risk of cancer.

Take home message:

Go out there and enjoy your cups of coffee - but try to limit your intake to 2-3 per day for men, and possibly slightly more for women - and reduce your risk of suicide and heart disease/stroke (and possibly cancer). And of course don’t smoke. But always keep your eyes open for any drug/treatment - including ones you don’t think of as a drug like coffee, for a J curve, or a U curve (or inverted U). It is all about dosing - don’t get up to the 8 cup range (and remember to include ALL caffeinated beverages when you are calculating your daily total).

Heck - when you sum it all up coffee might be a longevity treatment that results in the coffee drinker living longer - since it reduces the leading cause of death (cardiovascular: #1 is heart disease, # 3 stroke), potentially the # 2 killer - cancer, and the # 11 suicide. And I didn’t have time to cover coffee’s positive effects on some of the others like diabetes (# 6)  and Alzheimer’s disease (# 7).

Enjoy your coffee today.

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