Cholesterol: A Medical Controversy – I Background

Cardiovascular disease is the #1 cause of death in the developed world, and for more than 50 years, standard medical advice has been that the best thing we can do to lower our risk of CVD is to reduce saturated fats in our diet.  The theory is that saturated fats lead to higher concentrations of cholesterol in the blood, and cholesterol in the blood leads in turn to formation of blockages that cause heart attacks.  There is strong, science-based opposition to this thesis, however.  Both parts of the inference have been attacked:  that saturated fat intake does not increase serum cholesterol, and that serum cholesterol does not cause heart attacks.


When my daughter was still in kindergarten, her pediatrician told us that her blood cholesterol was high, that she probably had a congenital predisposition to high cholesterol, and that we should begin early to modify her diet to moderate her risk of hert disease later in life.

Now my daughter is 28 and she asked me last week if she should be eating less chocolate and coconut to protect her long-term health.  I knew enough to know that the answer to her question was a subject of deep controversy, and I didn’t know where I stood on the subject.

In my daughter’s honor, I am devoting this week and next to researching cholesterol and will report the results here.  Here are some questions I set out to answer.  (Please post comments suggesting your own).

  • If your cholesterol is high because of diet, does this lead to increased risk of heart disease?
  • If your cholesterol is high because of your genes, not diet, does this lead to an increased risk of heart disease?
  • Does consumption of saturated fats lead to higher levels of blood cholesterol?

These questions are elementary and the legitimacy of watching and treating blood cholesterol levels depends on the answers.  Assuming there is reason for “yes”, there are further questions:

  • What foods contribute to high/low cholesterol levels?
  • Are there supplements that help to lower cholesterol?  If so, what is their effect on overall mortality risk?
  • How does treatment with statins compare to treatment with diet and supplements?

It has been standard practice among doctors for the last 50 years at least to treat serum cholesterol levels as a risk factor for heart disease, and to assume that there is a causal connection.  Half of Americans over 65 are taking prescription statin drugs (and ⅙ of people between 45 and 65) [ref].  It’s clear that statins lower cholesterol in the blood, but whether the drugs lower risk of heart disease is less clear, and there may be no benefit at all for overall mortality rate [ref].

The above questions are difficult because there is such a deep division of opinion in the medical community.  The mainstream view, which has the best data and the best studies behind it, is also suspect, in my mind, because so much of the science has been funded by the pharmaceutical industry.  Statin drugs are a $35 billion dollar industry in America, growing rapidly, and I have seen an estimate as high as $200 billion per year worldwide.


Differences in evaluations of statin drugs are stark

Here is a semi-popular report published by Harvard Medical School health blog.  Peter Wehrwein notes that statin use is rising rapidly and heart disease deaths are falling rapidly.

A meta-analysis published in Journal of the American Medical Assoc (1997) concluded: “This overview of all published randomized trials of statin drugs demonstrates large reductions in cholesterol and clear evidence of benefit on stroke and total mortality. There was, as expected, a large and significant decrease in cardio-vascular mortality, but there was no significant evidence for any increases in either non-CV deaths or cancer incidence.”

A nutrition conference in Copenhagen (2010) produced the take-home message that every time an individual replaces 1% of the saturated fats in his diet with poly-unsaturated fats, his blood cholesterol decreases enough to afford a 2 to 3% reduction in risk of heart attack.

On the other side, here is the conclusion of a meta-study (2010) also published in the JAMA, pulling together results from 11 different studies over 40 years:  “This literature-based meta-analysis did not find evidence for the benefit of statin therapy on all-cause mortality in a high-risk primary prevention set-up.”  Dr Fred Kummerow, author of Cholesterol is not the Culprit, was featured by Dr Mercola this week. “Over the past 60 years, his research has repeatedly demonstrated that there’s NO correlation between high cholesterol and plaque formation that leads to heart disease Dr. Kummerow’s work shows that it’s not cholesterol that causes heart disease; rather it’s the trans fats and oxidized cholesterol that are to blame.”

Opposition to the standard hypothesis (saturated fats => High LDL => Stroke and heart attack) is not limited to the “natural medicine” community.  It is broad and varied, some of it well-rooted in standard methodology of biochemistry and epidemiology.

“A meta-analysis of prospective epidemiologic studies showed that there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD or CVD.” (2010)

I know of no other place in standard medical practice where the gulf between credible, opposing viewpoints is so vast.  I will continue to read, and next week promise to report what I can about why the disagreements are so deep and the contradictions so stark.


Basic chemistry

Petroleum oils are simply chains of carbon atoms surrounded by hydrogen.  Each C can make 4 bonds, so most of the C’s in the middle attach to one C on each side and two more H’s.

Organic oils and fats are “fatty acids”, which means that they differ from the simple chains by the addition of an “acid group” on the end.  An acid group has two extra oxygen atoms, and is written COOH.

These are all saturated fats, meaning “as much hydrogen as the carbons can hold”.  This makes more sense when we define an unsaturated fat as one that has double-bonded carbon atoms. Some C’s instead of being attached to 2 C’s and 2 H’s have only 1 H.  They still have 4 bonds total, so they devote an extra bond to each other – a “double bond” between C’s.

Double bonds are more chemically reactive.  It is easier to break the chain at a double bond than at another place along the chain where there are only single bonds, and so fats with double bonds are more easily oxidized during cooking than saturated fats.  Unsaturated fats have a lower melting point, and are likely to be liquid at room temperature.

Omega 6 and omega 3:  These designations refer to the location of the double bond.  Omega 3 means that the 3rd bond is double, counting from the tail end, or omega end of the chain.  (The COOH is the head or “alpha” end; the opposite end of the chain is the tail or “omega” end.)

Trans fat:  Here’s a curious and useful fact from chemistry: the atoms in a molecule are always vibrating, wiggling and bouncing around.  Part of this is rotation around each bond.  Single bonds can rotate freely.  But double bonds cannot rotate. This means that the double bonds create the possibility of two different forms of a molecule.  The part of the chain on the right and the rest of the chain on the left of the double bond can be on the same side, creating a bent, V-shaped chain.  This is the “cis” form.  Or the two parts of the chain can be on opposite sides, so the double bond appears as just a kink in the chain, but not a bend.  This is the “trans” form.

This is the “cis” form of oleic acid

In nature, one finds mostly “cis” fats.  Trans fats are mostly manufactured in food processing

This is a double bond in the “trans” configuration. There is no bend in the chain.

Trans fats have a little kink in the chain, but the chain is basically straight.  “Cis” fats are V-shaped molecules with a bend in the middle.


Cholesterol is an essential, multi-purpose chemical, manufactured and used by every animal species and every cell within the animal.  Cholesterol gives cell membranes their pliability, and it is also used as a raw material for synthesis of hormones within a cell.

The molecular structure is much more complicated than the fatty acids described above.  It contains four linked rings of carbon atoms, and one OH group in the lower left corner, making it technically an alcohol.

Since cholesterol has very limited solubility in water, it is carried around in the blood by lipoproteinmolecules that attach onto the cholesterol molecule at one end and dissolve in water at the other end.  High density lipoproteins (HDL) are called “good cholesterol”, and low density lipoproteins (LDL) are called “bad cholesterol”, but whether this blood constituent is actually related to risk of heart disease remains in dispute.

GDF11: A hormonal candidate for rejuvenation

I did a series last fall [1, 2, 3] on the thesis that aging is a program of self-destruction, executed under the control of hormonal signals in the blood.  If we can re-balance those signals appropriately, we will be able to revert the body to a younger age.  Maybe.  Yesterday, just in one day, three papers appeared in major journals reporting on blood factors that can reverse aging.

All three papers come from a line of research called parabiosis.  Circulatory systems of a young mouse and an old mouse are surgically joined so that the blood circulating in the veins of the old mouse comes half from the young mouse.  The finding from the Conboy Lab in 2005 is that the old mouse is rejuvenated in significant ways.  Research since then has sought to separate which factors in the blood are responsible for this effect.  Irina Conboy told me last month she has identified 6 key molecules, some of which need to be added, others either removed or de-activated.

Paper #1: (out of Stanford and UCSF and the Palo Alto Center for Regenerative Medicine) “Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level.”  Exactly which chemical compounds was not determined, but the benefit was seen both in growth of new neurons in the brain, and also in oberved behavioral changes and improvements in learning among the older animals.  The mechanism was traced to biochemical effects in the hippocampus, part of the old mammalian brain that is the first to be damaged in Alzheimer’s disease.  In case you’re wondering how you measure cognitive behaior in a surgically-creaed Siamese twin, the answer is that the group was able to see the cognitive benefits when small amounts of the young mouse blood were injected intravenously into the old mouse, eliminating the need for surgerical pairing.

The other two papers were announced in on-line news from Science Magazine, but the original papers are embargoed until Friday.  Both involve GDF11, (for “Growth-Differentiating Factor”), which is a hormone common to mice and humans.  “GDF11 is naturally found in much higher concentration in young mice than in older mice, and raising its levels in the older mice has improved the function of every organ system thus far studied.” [Doug Melton of Harvard, quoted in Science Daily]

Paper #2: (from Lee Rubin’s group at Harvard) Improvement in l earning behavior and increase in new neurons were both noted with injections of GDF11. “Regardless of the age of the old brain . . . young blood is still able to rejuvenate the aged brain.”  “We do think that, at least in principle, there will be a way to reverse some of the cognitive decline that takes place during aging, perhaps even with a single protein. It could be that a molecule like GDF 11, or GDF 11 itself, could” reverse the damage of aging.” [quoted in Science 2.0]

Paper #3: (from Amy Wager’s group at Harvard) also used GDF11, and demonstrates improvements in healing and in muscle growth and strength. “Injections of GDF11 can reduce the thickening of the heart that typically comes with aging in mice…GDF11 works nearly as well as parabiosis in helping aging mice recover from a muscle injury and boosts their performance on running and grip strength tests.”

When dramatic results like this, indicating that some simple intervention is capable of turning back the aging clock, the question everyone avoids asking is, “Why isn’t the body doing this on its own?”  The answer, of course, is that the body doesn’t want to.  The body is programmed in its genes to age and die, but to acknowledge this is to precipitate a revolution in our understanding of the fundamental mechanisms of evolutionary biology.


Turmeric > Curcumin

Curcumin is extracted from the turmeric root, a common Indian spice with a long tradition of healing applications.  Turmeric is about 2-5% curcumin.  It is a robust anti-inflammatory agent, and it signals cancer cells to eliminate themselves.  Evidence from several modalities suggests that curcumin protects gainst Alzheimer’s Disease.  Can it also help us live longer?


Begin with the idea that inflammaging is one of the four programs of self-destruction which take over our bodies later in life.  Quelling the body’s inflammation is one of the best anti-aging strategies we have, and curcumin is the most effective herbal anti-inflammatory agent we know.  It couldn’t be clearer…

But look below the surface, and things are more ambiguous, more complicated as usual.  Yes, I believe that curcumin has a place in a longevity program, but how much to take? and in what form?  These are questions that only get more difficult in the light of hundreds of studies, some with results that are contradictory in crucial ways.

The first mystery about curcumin is that there is a long tradition of turmeric root in Ayurvedic and Oriental medicine, yet hardly any curcumin is absorbed from the stomach.  Are there other compounds in the turmeric root that facilitate absorption of curcumin?  Or maybe curcumin is not the only beneficial ingredient in turmeric.  There is a lot of literature documenting the metabolic effects of curcumin, but only one study I could find that compared curcumin to whole turmeric (and some of its reported findings were so strange that it makes me suspicious of everything in this paper).

First, the benefits:



Curcumin acts by a similar mechanism to aspirin and other NSAIDs, inhibiting COX chemistry that promotes inflammation.  In addition, curcumin suppresses the action of NFkB, a signaling chemical that promotes inflammation, and increases in prevalence as we age, to our detriment.  This is theoretical ground for believing that curcumin can do something that aspirin does only weakly, so curcumin may have benefits even for those who are already taking daily aspirin or ibuprofen.  There are also some rodent experiments [ref, ref] suggesting that aspirin + curcumin is better than aspirin alone.

I have written that anti-inflammatory supplements are the easiest and surest longevity program currently available.  Surely curcumin finds a place in this program.


Anti-Cancer Activity

Curcumin has been demonstrated to kill cancer cells grown in the lab [ref, ref, ref, ref].  In mice and rats, oral curcumin has been shown to prevent cancer [ref, ref, ref], and in humans there have been some small epidemiological studies.  A search of produced 97 studies, about a third of them involving cancer.  Cancers of the digestive tract are most likely first targets, because of the difficulty of getting curcumin into the bloodstream.


Alzheimer’s Disease

Evidence that curcumin protects against AD is even stronger than for cancer.  There has been extensive experimentation with cell cultures [ref] and with rodents [ref], and in addition there is the human epidemiology, linking consumption of curry spices to protection against AD.  Age-adjusted incidence of AD is far lower in India than in America ([Ref] compiled separately for people with different alleles of the gene APO-E) and the difference has been statistically linked to eating curry [Ref].  Often I am skeptical of cross-cultural comparisons, because so many differences are difficult to untangle, but in this case, understanding of the underlying biochemistry is so strong that I think the attribution to curry is probably warranted.

Since turmeric is only about 10% of curry, and curcumin is only a few percent of turmeric, and curcumin absorption in blood tests is less than 1%, it would be predicted that the amount of curcumin that is absorbed by people who eat curried foods ought to be too small to matter, and yet it doesmatter.  I take this to mean that there is something we don’t yet understand about turmeric’s mechanism of action.  In addition, there is at least one known synergy between turmeric and other spices that might be eaten with it: black pepper increases the staying power of curcumin in the bloodstream (more below).



For the last decade, it has been acknowledged that osteo arthritis, like rheumatoid arthritis, is better described as an auto-immune disease than as a wearing-away of cartilage.  This would seem to be a natural application for curcumin, but study has just begun.  [Example]


Curcumin and cardiovascular disease

Also: whole turmeric is a vaso-relaxant [ref].  This means that eating turmeric might protect against heart disease in the near term.  In other columns, I’ve tried to make the distinction between slowing the aging process and cutting the immediate risk of mortality.  Of course, both are valuable.  Aspirin, for example, slows aging by damping inflammation, and also cuts the risk of stroke and heart attacks in the near term by reducing blood clots.  In that curcumin is an anti-inflammatory agent, it may slow the aging process.  To the extent that curcumin makes arteries more pliable, curcumin might also lay claim to reducing mortality, and by a different mechanism from aspirin, so that we might hope the effects (aspirin + curcumin) are additive.


Warning: Telomerase inhibitor

Part of the mechanism by which curcumin kills cancer cells is to inhibit telomerase.  Does curcumin also inhibit telomerase in healthy cells?  We need telomerase to keep our stem cells healthy into old age, so this is potentially a pro-aging function of curcumin.  I have found no data on the effect of curcumin on telomerase expression in healthy, non-cancerous cells  Note: after having written the above, I learned today that  Curcumin does not inhibit telomerase in healthy cells.  My sources are Bill Andrews, whose company, Sierra Sciences has assayed hundreds of thousands of substances for telomerase activity in vitro, and Jim Green, whose story I wrote about a few weeks ago.

Life Span Experiments

There is exactly one (אחד) (один) (واحد) (1.000) study in which mice fed curcumin** lived 10% longer [2007] and one (ένας) (ایک) (I) (ஒன்று) study which found no effect on mouse life span [2013].  There are many possible reasons the two well-respected research groups might have obtained different results.


Absorption and the fundamental mechanisms of action

It seems to be a common experimental finding that, after dosing a subject with turmeric or curcumin, no curcumin can be detected in the blood – and yet the full therapeutic benefit is being realized [Examples 1, 2, 3].  In some studies, curcumin could easily be found in urine samples, but was undetectable in the blood.  This situation suggests to me that something basic may be missing from our understanding of the metabolic chemistry of turmeric and curcuminoids.  Curcumin was identified more than 200 years ago as the active ingredient in turmeric, and most research up to this date has been designed and interpreted as though nothing else mattered but delivery of curcumin into the blood and thence into the body’s cells.  But perhaps there are metabolites that we have yet to identify, or perhaps a combination of chemicals acts synergistically.

A great deal of work has been done in recent years that is narrowly focused on delivery strategies that raise measured levels of curcumin in the blood.  This activity is commercially motivated.  Here is a promising herb that is cheap* and un-patentable, so companies are clamboring  to distinguish their products with proprietary processing for increased absorption.  But it may be that we don’t know enough yet to be sure that curcumin is all that matters, or that higher blood levels for longer times translate into better effectiveness.

Two issues of bioavailability are discussed in this this 2007 review:  First, inability to cross the stomach lining into the blood; second, the liver efficiently removes curcumin from the blood and breaks it down before it can be effective.  Liposomes address the first issue.  A liposome is a microscopic bubble of edible oil (“lipid”) which can carry a small quantity of chemical payload across the stomach wall.  Piperine (a chemical constituent of ordiary black pepper) addresses the second issue [ref], slowing breakdown of curcumin in the liver.  A phytosome is a liposome that contains a payload of multiple chemical species, and phytosomes are commercially available that combine curcumin with piperine.

Three formulations of curcumin with enhanced bio-availability are sold as Mervia, BCM-95 and Longvida.  All three use liposome microencapsulation, and include different proprietary ingredients and processes.  Dr Trutt describes the three, and recommends Longvida, based on indirect reasoning: Longvida has the most credible data for getting curcumin into the bloodstream, and only curcumin has been shown in lab tests based on cell biology to protect against Alzheimer’s Disease.  He may be right, but I would like to see some human or animal studies, since there are often surprises in the inference from cell culture to whole animal.

I wish

I wish there were more research on components of turmeric, together and separately; less on curcumin in isolation.  I wish there were more research with health and longevity as measured outcomes, less emphasis on blood levels of curcumin.

Until we have much better understanding, I’m going to suggest that whole turmeric with black pepper is the most conservative path to supplementation.  It tastes great with eggs.


The bottom line

Turmeric, with its main active ingredient curcumin, is a potent anti-inflammatory agent with evidence suggesting that it can lengthen human life span, while protecting against cancer and Alzheimer’s disease, and possibly cardiovascular disease as well.  Most of the benefits overlap with aspirin/NSAID.  For those who prefer not to take NSAIDs because of stomach issues or because of a preference for “natural” products, turmeric provides unequivocal benefits.  And even if you are already taking NSAIDs, there are probably some additional benefits from turmeric.

Large quantities of turmeric are the most conservative and the cheapest form.  If you’re thinking in terms of daily supplementation, teaspoonsful of turmeric may be the least convenient form; but if you like Indian cooking, it may be the most convenient way to dose yourself with turmeric.

Turmeric has a long and venerable history, and it is not entirely clear how the different chemical components of turmeric might interact.  Eating turmeric with a small quantity of black pepper greatly increases the body’s uptake.

There is research to indicate that curcumin is the most important active ingredient, and concentrated curcumin can be taken conveniently in a pill that is twenty times smaller than the portion of whole turmeric from which it is derived.  Absorption into the body is still an issue, and there are various commercial formulations of curcumin that claim to have resolved this issue, supported mostly by in-house studies.

If you are taking telomerase-activation supplements, then there is potential for curcumin to interfere with their action.  Whether this is a serious problem is not known, but to be safe you may want to alternate telomerase activation with curcumin, for example on a cycle of 3 to 8 weeks.



Thanks to Steve Ellis of Edible Science for suggesting that I look into curcumin, and providing references and links.  The views expressed here are mine and not his.


* $4 per pound of turmeric in bulk.  This works out to about 25c per gram of curcumin.  Even the liposomal product BCM95 is still only about $2.00/g retail.

** Actually a metabolite of curcumin, called tetrahydrocurcumin, which seems to have borrowed the abbreviation THC from a better-known substance.