[ed. note: We’ve been privileged to share with you some “non investment” commentary here from Michael Jorrin, a longtime medical writer who we like to call “Doc Gumshoe” — today he’s got a new piece for us that should help us think skeptically about yet more of the “easy solution” promises people make about health, usually when they’re trying to sell you the latest hot supplement or drug … and, as always, we need to remind you that the opinions from Doc Gumshoe are his own, we’ve done no more than a bit of light editing to prepare his piece for you today. Enjoy!]

Drink your pomegranate juice and eat your blueberries! They’re antioxidants, and antioxidants are good for you, because they combat free radicals (whatever those are) and free radicals are truly evil, because they cause all manner of diseases and are the underlying causes of aging, and if we could eliminate the free radicals, we could live a really long time.

That’s the Received Wisdom, and I won’t argue with it, because there’s certainly an element of truth there. How large or important that element of truth is remains to be seen. Let’s take this catechism one bit at a time.

Free Radicals: What Are They, Anyway?

First, what are free radicals? They are not bomb-throwers who have evaded prison, but small ionized chemical entities that are avid to combine with whatever they can latch on to. Consider saltpeter, chemical name potassium nitrate, chemical formula KNO3… Saltpeter is used as a food preservative, particularly in cured meats, and supposedly was put into the food of boys in boarding school, soldiers, and other young libidinous males in order to curb their natural instincts. When potassium nitrate enters solution, such as the human bloodstream, it immediately ionizes, meaning that the potassium part and the nitrate part swim around independently. The potassium ion has an extra electron in its outer shell, so it is K+, and the nitrate part is missing that outer electron, so it is NO3 –. The NO3 – ion is a free radical, and it seeks to combine with other entities from which it can grab that missing electron.

Saltpeter is just a single example of the kinds of substances that we’re exposed to that can create free radicals. All kinds of substances can lead to free radical formation – anything that can release ionized oxygen, hydroxyl, hydrogen peroxide, or other oxidizing ions. The worst offender is cigarette smoke, and there are many more in our environment. In the process of swiping electrons, free radicals can affect and perhaps damage human cells, including their DNA. If the damaged cells merely perish, that’s no big deal – cells die all the time and are replaced by new, healthy cells. But if cellular DNA is damaged, the successor cells themselves may be damaged or even cancerous. That’s the chief threat posed by free radicals.

What Do These Wonderful Antioxidants Really Do?

Antioxidants counteract the effects of free radicals by offering themselves up as targets, sparing some of the human cells that the free radicals might otherwise have damaged. There are lots of antioxidants in the food we eat, not just pomegranates and blueberries and cherries and carrots. The question is, are these dietary antioxidants sufficient?

There are those who answer that question with a resounding “NO!!!” (Many of these folks are the makers and marketers of antioxidant supplements, so they may not be totally disinterested.) Whether this view is completely fact-based or not, it plays nicely into a common tendency, which is that if a bit of something is good for you, then more of that same something is probably even better for you. Advocates of antioxidant supplements point out that, while antioxidants in our food may have been sufficient in times past, we’re exposed to so many more free radicals than our ancestors were that we need supplemental antioxidants.

In the case of antioxidants, this is open to question, at the very least.

So, what are antioxidants? The antioxidant substances in those useful (and pretty good-tasting!) foods are flavonoids, carotenoids, polyphenols, and others. Carotenoids, especially beta-carotene, are precursors of vitamin A, and vitamins C, and E are themselves antioxidants.

Dietary Antioxidants vs Antioxidant Supplements

The evidence that dietary antioxidants help prevent disease is quite strong. For example, there was a large study in Sweden, which followed more than 30,000 women for more than 11 years. The total study population was divided into fifths, and the study found than the women who consumed the most antioxidants in their diet (the top fifth) had an incidence of heart failure that was about 60% of that in women who consumed the least antioxidants (the bottom fifth). Heart failure is a pretty good indicator of many health factors, since several factors contribute to heart failure – high blood pressure, elevated cholesterol, diabetes, and obesity.

However, when it comes to antioxidant supplements, quite a lot of the evidence points the other way. For example, a study in current smokers who were given beta-carotene supplements found that these appeared to increase rather than lower the incidence of lung cancer.

The vitamin E question is particularly complex. The antioxidant found in vitamin E supplements is alpha-tocopherol, while the vitamin E antioxidant found in food is gamma-tocopherol. Vitamin E in the diet may reduce the risk of heart disease and cancer. Not so with vitamin E supplements, perhaps because of the difference between the alpha- and gamma-tocopherol.

In fact, rather than being beneficial, antioxidant supplements may increase rather than decrease mortality.

The most convincing evidence comes from the Cochrane Collaboration, which is an international organization (28,000 contributors from 100 countries) that reviews clinical trial data from all over the world and scrupulously creates analyses that pool the data from multiple trials. Cochrane reviews are generally regarded as the gold standard.

Cochrane conducted a systematic review of studies evaluating the benefits of antioxidant supplements, including beta-carotene, vitamins A, C, E, and selenium. They reviewed 78 studies with 296,707 participants, and found that overall, antioxidant supplements significantly increased the risk of death. In the 56 trials that they evaluated as having the lowest risk of bias, antioxidant supplements increased the risk of death by about 4%. That may not sound like a huge increase in the risk, but when we consider that antioxidants are supposed to prevent disease and death, and the data tell us that that they do the contrary, that should give us pause. And, by the way, this was true for each of the individual antioxidant supplements included in the study.

Why This Apparent Contradiction?

What might account for this paradox? One possible mechanism is that, while it’s accepted that free radicals might trigger the mutations that initiate the growth of cancer, there is some evidence that free radicals also preferentially attack cancer cells rather than non-cancerous cells. So perhaps in a healthy person, reasonable amounts of antioxidants in the diet might reduce the number of newly mutated cancer cells. However, once cancer cells are present, (as in the study in smokers mentioned earlier), free-radicals might keep cancer growth in check, and antioxidants might stymie their mission.

So the question looms: what’s the right balance between free radicals and antioxidants? This is the Goldilocks Question: how much is Just Right? With regard to the free radicals versus antioxidants question, it seems to me that the Just Right option is plenty of dietary antioxidants, but go easy on the supplements.

It does appear that free radicals serve some essential function, and we don’t want to eliminate them from our bodies – nor can we, since some free radicals are actually created in our white blood cells (neutrophils and macrophages) and help to kill and scavenge bacteria, protecting us from some infections.

The Goldilocks Principle and the Search for Just Right

However, the Goldilocks Question applies to almost everything in our lives. Everybody, and I really mean everybody, knows from experience that we lowly humans are comfortable only in fairly narrow range of conditions. For example, our normal body temperature is 98.6° F (37.6° C). But if we climb into a bathtub that’s at 105° F, it feels really, really hot. And if it goes much below 95° F, we might run a bit more hot water to get it to feel just right, so that Goldilocks would be happy in the tub.

The same question can be asked of many other things – such as the Just Right amount of salt in our diets, our optimum weight range, how much alcohol should we consume, and on and on.

The Salt Question

The salt question has resurfaced fairly recently. For quite a long time, the doctrine of the health authorities (such as the U. S. Centers for Disease Control and Prevention) was that most people should consume not more than 2,300 milligrams of salt per day, and that people at risk for heart disease should limit their salt consumption to not more than 1,500 milligrams per day. That’s not much salt – maybe a bit more than half a teaspoonful.

The reason for this edict is that salt (or, actually, sodium ions) tends to raise blood pressure, and high blood pressure, as we all know, leads to heart disease, diabetes, and strokes.

But the CDC has changed its tune, based on research that has emerged since their recommendations, which they issued back in 2005. A committee convened by the CDC reviewed the current evidence and pronounced that there is no reason for anyone at all to try to limit their salt consumption to less than 2,300 milligrams per day, and pointed out that when salt consumption is pushed below that level, not only is there no benefit, but some people may begin to experience actual adverse consequences.

A common assumption is that if too much of something is bad for you, then the best thing is to have as little as possible. This is the reverse of the assumption that has been made about antioxidants, that if some is good, more is better. But the Goldilocks Principle holds that we have to look for the amount that is Just Right.

In the case of salt, we can point to a couple of studies. In one, conducted in Italy, two groups of patients with congestive heart failure were assigned to diets with different quantities of salt. One group consumed 2,760 milligrams per day, and the other consumed 1,840 milligrams per day. The patients that consumed the smaller amounts of salt in their diet had three times the number of hospital admissions and twice as many deaths as those that consumed the higher amounts of salt.

Another larger study followed nearly 30,000 patients with hypertension for nearly 5 years and tracked their salt consumption by analyzing urine samples. In that study, the risk of clinically important cardiac events, including deaths, was significantly higher at the two ends of the scale – patients consuming more than 7,000 mg per day and those consuming less than 3,000 per day. So, based on those data, the Just Right amount of salt is somewhere in between those two numbers.

I should mention here that the average sodium consumption in the US, and elsewhere for that matter, is about 3,400 milligrams per day. Is that too high? The American Heart Association still thinks so, in spite of the new CDC recommendations. A concern is that what lots of people will take from the new data is that salt just doesn’t matter, and they can use as much as they want. But that, too, is a violation of the Goldilocks Principle – what we’re looking for is the Just Right amount of salt.

(By the way, I might add here that the biggest users of salt in the American diet are not cooks in the home kitchen nor yet people who sprinkle it on at the dinner table, but salty packaged food products.)

None of this research denies the well-established link between excessive salt consumption and hypertension. What it points to is that low sodium levels have some clear harmful consequences – triglyceride levels rise and insulin resistance increases, with potential adverse cardiac consequences. We can’t judge salt consumption just on the basis of its effect on blood pressure.

When It Comes to Blood Pressure, Is There a Just Right Level?

Speaking of blood pressure, the Goldilocks Principle applies there as well. Blood pressure is carefully adjusted by many homeostatic responses so that mean arterial pressure is about 100 mm Hg. Mean arterial pressure is just what it sounds like – halfway between the pressure at the moment when the heart contracts to force blood into the arteries and when it relaxes to accept more blood from the veins. That pressure, 100 mm Hg, is about 13% higher than atmospheric pressure at sea level, which is 760 mm Hg. We need that relatively small degree of additional pressure to keep the blood circulating throughout the body.

However, supposing your blood pressure was only 10% higher than atmospheric pressure, say, a mean arterial pressure of about 75 mm Hg, which might translate to 100/50 mm Hg. That 50 mm Hg value for your diastolic blood pressure is a shade too low. You’re running a risk of keeling over in a faint, because your heart can’t pump blood into your brain.

Of course, as soon as you do keel over, your heart isn’t pumping blood against gravity so much, and you’ll come to pretty quickly, and if you didn’t come down too hard, you’re probably fine. But that tells you that the little 3% difference between just right and too low can be important.

How About Weight and Body Mass Index?

Wasn‘t it Wallis Simpson, the Duchess of Windsor, who said “You can’t be too rich or too thin?” I don’t know about too rich – I’ll let you know if I ever get there – but you can definitely be too thin. The term for being excessively thin is cachexia; a condition that is seen in such diseases as cancer and AIDS, but that may also occur in persons who are obsessed with losing weight, e.g., some fashion models. It’s a risky condition, and can be fatal.

Of course, at the other end of the spectrum, we all know about the risks of being too fat. But is there a Goldilocks Principle here, and what does it point to as a Just Right body mass index (BMI)? Well, there’s a range, of course, but some data points to a Just Right range that’s considerably higher than the Received Wisdom.

In case you’ve forgotten, the official BMI ranges are: below 18.5, underweight; 18.4 – 24.9, normal; 25.0 – 29.9, overweight; over 30.0, obese. Taking yours truly as an example, I am 6’ 3” and I weigh about 217 pounds, so my BMI is 27.1 – in the middle of the overweight category. If I weighed 180 pounds, my BMI would be 22.5 – normal. To be underweight, I would have to weigh about 140 pounds. I haven’t been that skinny since I was a sophomore in high school, and I was really, really skinny then.

However, there’s pretty convincing evidence that those BMI ranges are flat wrong. An analysis of 40 studies looked at BMI and calculated the risk for both overall mortality and cardiovascular mortality, compared with normal weight subjects, which for this study was defined as BMI 20 – 24.9. No surprise – very obese individuals, those with a BMI over 35, were at very high mortality risk – about 10% higher total mortality, and 88% higher cardiovascular mortality. But persons with BMI values below 20 were also at very high mortality risk – 37% higher total mortality (higher than the very obese!) and 45% higher cardiovascular mortality.

What about the overweight and the obese? The merely overweight were at the lowest risk for both total (13% lower) and cardiovascular mortality (12% lower). And the obese in the 30 – 34.9 BMI range were essentially at the same risk as the normal weight subjects.

So, based on that study, which, by the way, came out of the Mayo Clinic, and included data on more than a quarter of a million subjects, the healthiest weight range is what the BMI classifies as “overweight.” The authors of the study suggested that it might be time to scrap the BMI as a risk factor. Applying the Goldilocks Principle, a bit overweight might be Just Right.

Is There a Just Right Level for Cholesterol, or Is Lower Always Better?

As far as I know, no one yet has determined what the Just Right number is for cholesterol, in particular LDL-cholesterol.

First, a word about nomenclature: we hear all the time about the good cholesterol and the bad cholesterol. I fear that those terms are just the way some health professionals try to avoid confusing us, but I think those terms are themselves confusing. I need to make the point that there is only one cholesterol, a fairly simple substance that has the characteristic of being solid at body temperature, and therefore, cannot by itself be transported in the bloodstream.

So, in order to get where it needs to go, which is just about everywhere in our bodies, cholesterol is gathered up in little bundles called lipoproteins. Some of the lipoprotein cholesterol bundles are large and loose – these are the low density lipoprotein cholesterol bundles, or LDL-cholesterol, or sometimes just LDL for short. Some are smaller, neater, tighter bundles – high density lipoprotein cholesterol, or HDL-C for short. The LDL bundles are the ones that tend to deposit cholesterol in our arteries, causing no end of trouble, therefore bad cholesterol, while the smaller HDL bundles transport cholesterol back to the liver and to the bile ducts for excretion, therefore good cholesterol.

We know what too high LDL-cholesterol levels are: in an otherwise healthy person, a reading of 190 milligrams per deciliter is way too high, placing that person at risk for heart disease. In persons with LDL-C levels greater than 190 mg/dL, treatment with a cholesterol-lowering drug, generally a statin, is recommended. Depending on risk factors, LDL-C levels as low as 100 mg/dL can trigger drug treatment, and in patients with established coronary heart disease or the equivalent, an LDL-C goal below 70 mg/dL is recommended.

So far, as regards cholesterol (whether total cholesterol or LDL-cholesterol) what has not yet been determined is How Low Is Too Low. Common sense (as well as current understanding of the role of cholesterol in our physiology) tells us that there has to be a Too Low level. After all, cholesterol is present in most of our tissues and is an essential component of most hormones; we synthesize most of the cholesterol in our system (only about 20% at most of our cholesterol enters our bodies as cholesterol), so clearly we need it. We just don’t know what the Just Right amount is.

A New Cholesterol-Lowering Breakthrough? We’ll See.

However, current drug development, being pursued pedal to the metal by at least four pharma outfits (Amgen, Pfizer, Regeneron, and Sanofi) may lead to a better understanding of the Just Right level for LDL-cholesterol.

It has been known for quite some time that some individuals have surprisingly low LDL-C levels – some young people are going around with LDL-C levels of 50 mg/dL or even a bit lower. These low LDL-C levels are likely due to a combination of genetics and life-style factors, and we don’t know much about the total health status of these individuals, other than that they’re in good health at the time. Have there been studies to follow these folks for another 25 or 50 years? I fear not – why would there be? We don’t go out of our way to look for trouble.

Just recently, though, a couple of individuals have been identified whose LDL-C levels are incredibly low – about 15 mg/dL. Their low LDL-C appears to be due to an almost freakishly unlikely genetic factor. These persons inherited mutated versions of a gene, designated PCSK9, from both parents. The PCSK9 gene, when working normally, is part of the physiologic process that unpacks LDL-C bundles and repacks the extra cholesterol they contain into HDL-C bundles for eventual excretion. When the PCSK9 gene is defective, some people develop excessively high LDL-C levels, and, as a consequence, are at high risk for cardiovascular disease.

But the mutations that these individuals with the really low LDL-C levels, rather than making these genes defective, had apparently made the PCSK9 genes super-effective. So pharma immediately saw a colossal opportunity, and launched research projects to develop drugs that would mimic the effect of these mutated genes. The drugs they have come up with are biologic drugs, which is to say, not simple chemical molecules, but complex drugs called monoclonal antibodies that attempt to duplicate the action of human agents produced by the immune system. Amgen has completed at least one Phase II trial in about 400 subjects, and their drug, designated AMG145 has demonstrated success in lowering LDL-C to 50 mg/dL in some subjects enrolled in the trials.

That would be enough for any pharma to mount a really big fireworks display, since no current drug or drug combination has achieved anything comparable. A person with high LDL-C, say 160 mg/dL, might bring it down to something in the neighborhood of 100 mg/dL by using a high dose of a statin. So a drug that would reduce LDL-C to half that level would be a huge step forward – in controlling LDL-C, at least!

Why do I stick in that slightly negative comment? Because we do not know the long-term consequences of living with an LDL-C level that low. The studies so far have not looked at clinical benefit – only at the change in blood LDL-C levels. Now, to be fair, the experience with lowering LDL-C has been, up to now, that heart disease risk goes down at the same time, so it would be expected that the same relationship between lowering LDL-C and heart risk would continue to hold.

But until this is confirmed by clinical trials with actual, concrete health benefits as outcome measures, we won’t know. I say this because of the Goldilocks Principle, which seems to apply in all kinds of areas where we human beings interact with the world around us. We saw what happens with antioxidants, salt, and our body mass index. We can’t assume that because some antioxidants in our diet are a good thing, more and more antioxidants are better. We can’t assume that because too much salt in our diets is bad, we should reduce our salt intake to almost nothing. We can’t assume that you can’t be too thin (I don’t know about too rich!) Similarly, we can’t assume that there are no health consequences to lowering LDL-cholesterol to previously almost unheard of levels. We’ll have to wait until we see whether those new drugs really do decrease heart disease, and whether there’s a minimum LDL-C level below which people might develop hitherto unsuspected problems.

Goldilocks is still waiting for Just Right!

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Doc Gumshoe looks forward to your comments, and, in particular, to any hints about topics that you’d like to hear more about. Remember that I am not a bona fide MD, but I do keep up with health news and medical literature and consider it from my naturally contrarian point of view. My best to all, Michael Jorrin