door opener, I’m finding that it unlocks/makes visible to the body’s consciousness deeply

hidden chemicals – pesticides, ie Kepone and heavy metals hidden in and compromising the

functioning of mitochondrial DNA – of glands, organs, neuronal tissue – ie thyroid, alveoli,

bronchioles, spleen, renal tubules, liver, small intestine – it opens the door for the body mind to

recognize the toxins – and once recognized – ie not hidden, the body dumps/detoxes it, thus

allowing mitochondria to function more effectively with full energetic expression.But I have seen over 30 or 40 years and have done what I can to get rid of a whole host of polio

viruses that were grown in chimpanzees. What I’m about to say to you is, since I’ve been using

Metadichol, they have in the last month to 2 months, they have gone from the RNA protein or

the DNA protein or mutated – those are the 3 forms – into now dead viruses. And it’s not just

that, it’s old mutated stuff – Hemolytic B, it’s smallpox, it’s varicella first starting out live, then

mutated, then dead, so it does do that.

It’s not the Godfather that tells the cells to shape up their asses; the cells have an enormous

consciousness. I think what it does is it shines the light on all the shit. And I’m finding it’s not

just viral or bacterial, it’s every single toxin, including radioactive Strontium 90, which I got a

huge dose of as a kid in New York and it’s including all sorts of heavy metals and it’s including all

sorts of pesticides. I think what it does is it shines the light, opens the door to the cell seeing

them, and then the cell knows already because they’re all conscious, to get rid of it and sweep

it out. That’s my take. I could be wrong but that’s my take on it. It makes the crap visible.

Let me give you one example. I have a massive menu but the menu has histological points,

Gamma 2 which are called neurological points and all sorts of other body points. Over many

years but especially over the last few months there’s been a huge amount of stuff clearing out

of my liver as other places clear; and I’m working two days ago and suddenly the word sinusoid

comes up. What it is, it’s not even a capillary. It’s tinier than a capillary and it’s in the liver, it’s in

the adrenals, it’s in the bone marrow and all sorts of sinusoids start showing up. But,

importantly, all sorts of toxic crap of the same sort that I’ve found shows up there, and the way

I do it is, when it’s recognized by me, through the menu, I write it down on a paper, I hold the

paper with the writing facing out, I tap the body and the body is going to start dumping it like

crazy. How do I know that? I know it but I have an incredible physical therapist who, when I’m

working and she works she’ll see all sorts of either toxins or infections pouring out.

But here’s the other interesting piece. The body hides things so that it can seal it around and

protect it until it’s ready to let it go. And if it lets it go in one place, it lets it go in other places.

So, Strontium 90 now is coming out from all over.

But the interesting and fascinating thing about Metadichol – Raghu speaks about five sprays

and I don’t doubt the science of his genius, but I have variously tested anywhere from five

sprays once/day when I started; now I’m at a point where I can be testing at times 50 sprays

five times/day and now 75 once/day; yesterday and the day before, 65 twice/day, and I trust

my testing and something is going on where the body is saying that’s what I need to get rid of

whatever this shit is. So, I’m putting this out there, not to dispute him but to suggest to you is

that it really could be a lot different, depending on the day, the moment and what’s being dealt

with. Now, this could just be my vehicle that needs, whatever it needs to do what it does.

And I said this to you when I met you; I’ve been at this with supplements, and this is the best

thing that will fix anything in the world. All the supplements I’ve taken are target specific, and

there’s a company called SpectraCell that I use for the consult for over 30 years, least amount

of supplements with the most effect; you can’t easily, palpably see what a supplement does.

You can’t say, “Oh, my God, it’s like the movie “Paul” – he touches her in the eye and her eye

heals instantly.”

And most people, when they have this; I can see it in a way that other people really can’t see it.

I can see what it’s doing, I can see what’s happened to my energy, my runs are better, I’m calmer in many ways. I mean there’s a lot of things that it does. I can see what it does inside in

terms of helping stuff, clearing stuff out. Mostly it’s my intent but this is the helper.

Beyond amazing – after years of bullshit, this is something beyond real.

Howard March, 2020

quantized to begin with. Are their more connections you should be aware of with the skin? Yes.

The integumentary system covers the surface of the embryo and its specialized skin structures

including hair, nails, sweat glands, mammary glands and teeth. As a system it has contributions

from all embryonic layers. This means that every system at some level is tied to Vitamin D in

some way, and it is why Vitamin D is important to understand.

In our adult form, the skin and our brain are no longer are ‘physically‘ connected. What binds

their function together physiologically? Vitamin D is the short answer. How? It does so by

action at a spooky distance. It is called the principle of non locality. Who came up with this?

Einstein. Where did he get the idea? He got it from the laws of nature based in the photoelectric

effect. This is how nature works at its fundamental levels. It is where the macrocosm of space,

meets the nanoscopic precision of the microcosm of a cell. Today, ‘modern organic chemists’ will

tell you they do not believe in action at a spooky distance applies to organic chemistry. It does.

There beliefs are another reason why medicine might still be in the dark over these issues.

Ulitmate Truth Bomb: Any physical theory that supersedes or replaces quantum theory must

make similar experimental predictions and must therefore also be non-local in this sense;

quantum nonlocality is a property of the universe that is independent of our description of

nature.

What you need to understand about this, is if this is light is a foundational element of nature

(and it is), then it means biology had to build a biochemical system around each of the elements

found in nature to its advantage in order to control the randomness of quantum effects to make

life possible. Vitamin D is part of that system that evolutionary biology constructed to do this.

The first biologic use of light is found in photosynthesis. Plant life used photosynthesis 3-3.5

billion years ago. Nothing found to date in any branch of science is more energy efficient on the

planet compared to photosynthesis.

Photosynthesis uses the quantum science of ‘water energy’ to its huge advantage. When light and

water interact in a plants pigments or in our carbon nanotubes in our skin some amazing things

happen. It is so complex and amazing but it explains how we transfer energy from the light in

our atmosphere that is carried on water vapors in clouds. The phase change of gaseous water to

rain is called a phase transition of water. When we move from a gas to liquid rain huge amounts

of energy have to be added to the water vapor to change it to liquid rain. When that liquid is

heavy enough in a cloud it falls to Earth via gravity. What controls this process? Sunlight, and

the water’s molecular chemistry it finds its current phases in using the science of dielectric

chemistry. When this phase transition occurs liquid water becomes rain, which then releases its

energy to grass and plants. This transfer fuels photosynthesis which turns atmospheric CO2 into

O2 for animals to use at 100% efficiency. This is why Oxygen exploded suddenly on the scene of

life 542 million years ago and life exploded. This was known as the Cambrian explosion.

When life harnessed the power of the sun via Vitamin D life exploded. Over the following 70 or

80 million years, the rate of evolution accelerated by an order of magnitude (as defined in terms

of the extinction and origination rate of species) and the diversity of life began to resemble that of

today. All present phyla appeared within the first 20 million years of this period. You would

have thought a bunch of smart bone collectors would have put two and two together by now.

They have not. Plants took full advantage of this. They exploded on the scene of life back then.

The photoelectric effect has been extensively studied in plants. It has been found to be massively

energy efficient. The rate of energy capture by the photoelectric effect in plants is immense. It is

approximately 100 trillion watts (1 trillion watts = 1 terawatt). This is ten times the current the

current power consumption of the human species today. It is clear the photoelectric effect was

very powerful for plant life that they could evolve just using water and light to make nutrients.

Animals are not connected into the ground 100% of the time, nor do they have their

semiconductors (canopy of leaves) in the sunlight 24/7. So animal life had to come up with a new

way to use the photoelectric effect to power life. It did. It used Vitamin D in our skin

semiconductors to transfer the sun’s power to our hypothalamus.

It turns our photosynthesis also gives animal life a boost too via its use of Vitamin D because it is

more energy efficient when it combines with the action of water in our carbon nanotubes in

shear production of energy.

So it appears animal life used some of the foundational ‘quantum pieces’ built into

photosynthesis in animals. The details on photosynthesis shows that photo-chemicals acts as

semiconductors in plants. So does collagen and water in animals. This is why a human can live

30 days without food but only 7 days without water. This is why plants need water to grow.

Water is one of the critical elements to life. What are the others according to scientists today in

NASA? Light and magnetism. This is why Mars is a dead planet and Earth is not. Mars lacks a

magnetic field and had its atmosphere stripped by the solar winds because of this lack of

protection. Animals began to construct energy systems via fractal design over eons and

connected multiple different biologic systems to make sense of the quirkiness of light and matter

to make life work. This is why the VDR is found in every human tissue ever sampled. We know

that Vitamin D and its receptor was designed to make perfect use the natural physical and

electomagnetic elements of light found on Earth around 600-700 million years ago. How it does

it, is now modern medicine’s mystery. Examine the simple physics problem and use it as an

analogy to explain quantum biology.

Shining light on the mystery

Einstein says, if you shine light and ultraviolet light on a piece of metal, the light can knock

electrons out of the metal. In a lab this data is easily collected and proven. Back in the early 20th

century, the photoelectric effect made science uncomfortable just like the story of Vitamin D is

today. The wave theory of light suggested as you turned up the brightness of the light, you

should eject more electrons, because brighter light has more energy in it. Why they had trouble

with Einstein’s ideas was because in their experiments this did not happen. If you shine light

onto a piece of an element, no electrons were ejected, no matter how bright the light was made.

But when you changed the light to violet, you could turn it down low and still electrons will be

ejected. Einstein’s genius was that he took the experimental data they created and made sense of

it without getting caught in their dogma. He realized that if light was made up of small particles

called photons, the photoelectric effect was easy to explain. Max Plank had shown in years prior

to Einstein’s ideas, that it was the frequency of light, and not the intensity of the light that

determines its energy.

The brain also pays attention to the frequency of light in our pineal gland;

Einstein’s original paper in 1905 suggested that low energy red photons do not have enough

energy to knock out any of the electrons out of the potassium and that was the reason the

experiments appeared to fail. He also pointed out that a single ultraviolet photon had enough

energy to knock the electron out. Why is this foundational principle important for Vitamin D?

Modern medicine is focused on sunlight being bad for us today. If you are following the Einstein

analogy, what if it is not the sun that is bad? What if it is the semiconductors that the sun acts

upon that is bad. If that were true and you did not know about these semi conductors, it would

appear that the sun was really bad for us. And that is precisely where modern medicine is today.

This is precisely how Neils Bohr figured out the mystery of the atom. He brainstormed to use

Einstein and Plank’s ideas and mix then with Balmer’s equation that described the emission

spectrum of hydrogen that was found in 1885. His idea was that electrons can only sit at certain

fixed quantum distances from the nucleus. When they become more energized they can move

further from the nucleus and if they really become energized they can be expelled in the form of

electromagnetic radiation. He essentially realized that the substance of matter really matters at a

particle basis. Since this is a foundational principle in nature it stands to reason that biology’s

uses the same principle.

It means that if the semiconductors are altered in terms of their ability to hold or transduce

energy it will have a direct impact on the effect of light on them. This may sound counter

intuitive to you at first, but it completely explains why we see a pandemic in Vitamin D now.

All eukaryotic life uses Vitamin D at some level in combination with collagen, Vitamin A, K, E,

and the RXR receptors and VDR.The vitamin D receptor plays an important role in regulating

the hair cycle. Loss of VDR is associated with hair loss in experimental animals and may help

explain why humans lost their body hair as they evolved close to the equator in the East African

rift zone. They likely needed the extra power of the sun to help power the epigenetic changes to

transform us from our ancestors because of the heavy energy costs our brain puts on the

mammalian body plan.

In humans it is well established that we use it to help form strong bones and to increase our

immune systems. When Vitamin D levels are low, it means only two things. It means the

frequencies of sunlight might have changed from the sun, or the detection system for the

spectrum of light is somehow altered in us. Since the frequency of the sun has been a constant on

this planet for 4.5 billion years we are left with the solution. When you have eliminated the

impossible, whatever is left becomes your new reality.

When one realizes that bone was quantized, look at what Einstein,Plank, and Bohr’s work

implied for biology, We have a Vitamin D pandemic today. It also explained why Vitamin D and

bone metabolism is tied at the evolutionary hip. Experiments also showed that collagen matrix

of bone acted as the N-type of semi-conductor of bone while apatite crystals were the P-type

semiconductor. We know that vitamin D plays a massive role in controlling bone metabolism.

How do humans make Vitamin D from the sun?

Non Geeks:

7-Dehydrocholesterol is the semiconductor in skin that takes the EMF signal of light and changes

it to a chemical signal that the brain samples to control circadian timing. It uses water as well.

Geeks: We humans use a specific frequency of the visible light spectrum to do it. It is called the

high energy UV B band of light to do it. This is precisely what Einstein pointed out

The back bone of Vitamin D is cholesterol made by every cell in the body that is converts to 7-

Dehydrocholesterol in the skin. The skin consists of two primary layers: the inner layer called

the dermis, composed largely of connective tissue, and the outer thinner epidermis. The thickness

of the epidermis ranges from 0.08mm to more than 0.6mm (0.003 to 0.024 inches). The epidermis

consists of five strata; from outer to inner they are: the stratum corneum, stratum

lucidum, stratum granulosum, stratum spinosum, and stratum basale. The highest

concentrations of 7-dehydrocholesterol are found in the epidermal layer of skin, specifically in

the stratum basale and stratum spinosum. The production of pre-vitamin D3 is therefore greatest

in these two layers, whereas production in the other layers is reduced.

Synthesis of pre-vitamin D3 in the skin involves UVB radiation which effectively penetrates only

the epidermal layers of skin. 7-Dehydrocholesterol absorbs UV light most effectively

at wavelengths between 290-320nm and thus the production of vitamin D3 will only occur at those

wavelengths. The two most important factors that govern the generation of pre-vitamin D3 are

the quantity (intensity) and quality (appropriate wavelength) of the UVB irradiation reaching the

7-dehydrocholesterol deep in the stratum basale and stratum spinosum. This is precisely what

Einstein said about the metal bench experiments. The parallel is congruent. Another important

consideration is the quantity of 7-dehydrocholesterol present in the skin. Under normal

circumstances, ample quantities of 7-dehydrocholesterol (about 25–50 mg/cm2 of skin) are

available in the stratum spinosum and stratum basale of human skin to meet the body’s vitamin

D requirements. Many drugs slow the formation of 7-Dehydrocholesterol. Statins are the best

modern example.

7-Dehydrocholesterol is the precursor of vitamin D3. Within the epidermal layer of skin, 7-

Dehydrocholesterol undergoes an electrocyclic reaction as a result of UVB radiation, resulting in

the opening of the vitamin precursor B-ring through a conrotatory pathway. Therefore,

Cholecalciferol is synthesized in the skin from 7-dehydrocholesterol under the action of

ultraviolet B light. Following this, the previtamin D3 undergoes a [1,7]

antarafacial sigmatropic rearrangement and therein finally isomerizes to form vitamin D3. It

reaches an equilibrium in the skin after several minutes depending on several factors including

conditions of sunlight (latitude, season, cloud cover, altitude), age of skin, and color of

skin.Cholecalciferol is then hydroxylated in the liver to become calcifediol (25-hydroxyvitamin

D3). Next, calcifediol is again hydroxylated, this time in the kidney, and becomes calcitriol (1,25-

dihydroxyvitamin D3). Calcitriol is the most active hormone form of vitamin D3.

Non Geeks: So why is Vitamin D low in everyone these days?

It is because the positive and negative semiconductors of the human body have become altered ,

globally for some reason. Moreover, the magnetic field our semiconductors find themselves in

today have also been altered. The reasons for the alterations are not the same everywhere on the

planet, but it is the ultimate answer. Moreover, some of us, like those in the western world have

multiple reasons that our semiconductors are altered. EMF, trans fats, man made foodstuffs like

soybean, canola, and vegetable oils, and fluoride in the water are just some There are many more.

These substances acts as dielectric blockers in biologic semiconductors. Dielectric blockers cause

avalanche collapse of energy transduction.

What is avalanche collapse?

Geeks: At breakdown, the electric field frees bound electrons and photons. If the applied electric

field is sufficiently high, free electrons from background radiation may become accelerated to

velocities that can liberate additional electrons during collisions with neutral atoms or molecules

in a process called avalanche breakdown of superconduction. Breakdown occurs quite abruptly,

typically in nanoseconds, resulting in the formation of an electrically conductive path and

a disruptive discharge through the material. For solid materials, like a liquid crystalline lattice of

water in a nanotube, a breakdown event severely degrades proton and electron currents, or even

destroys, its insulating capability.

Non Geeks:

When we understand this, we are back to Einstein’s math of the energy mass equivalence

equation of E=MC2. This also explains why no one really knows today what is the optimal

Vitamin D level in humans today. There is no group world wide who has normal semiconductors,

so we have no control group in which to study this properly. We have to rely on data collected on

humans pre- 1920 to really have an idea of what might be optimal. I have and this is why I like

the range of 70-120 ng/ml. Studies done of people of today will never be accurate to assess a good

Vitamin D levels for optimal health and will only act to fool physicians and patients.

Collagen is the the number one protein in the body by shear weight. It makes up the protein

sheaths and fascia that all carbon nanotubes are connected to. These tubes are all designed to be

filled with water. Collagen is what the negative semiconductor in most tissues, like bone

mentioned above. Some tissues can be the positive semiconductor. When the dielectric blockers

are added to collagen matrix for any reason, they can not make or transduce energy from

sunlight or any other quantum effect (electrons, photons, and phonons) and the end result that

we assay when we look is we see an alteration of our Vitamin D, DHEA, and HS CRP levels. You

might be seeing why Vitamin D levels are low in obesity and in metabolic syndrome now. These

two disease are the base of the sickness pyramid modern man faces today. Quantum biology

predicts that both diseases are underpinned by bad semiconductors that cannot hold their charge

for some reason. They are both diseases are disease were we have lost electrons, photons, or

phonons to the environment from our semiconductors,

This also explains why the paleo template helps improve your health to some degree. It also helps

explain why so many on the template do not get totally better to reverse their diseases. It is akin

to the physics experiment I mentioned to you above. There is more to the story, because there has

to be a way a reverse every disease since humans are not designed by nature to be filled with

disease. We need to approach our reasoning of modern diseases differently if we are going to

solve today’s conditions of existence. The paleo blueprint improves the collagen semiconductor

best because it increases the amount of protein to make collagen while cutting dielectric blockers,

that collagen uses in quantum semiconduction biology. But often times it does not go far enough

for those of us, whose diseases are tied to other semiconductors that are used in the brain, which

are made from DHA and water and not collagen. Osteoporosis, obesity, autism, depression, AD,

PCOS, and metabolic syndrome are some of these examples, but there are many others.

This is where the Epi-Paleo Rx steps up the game to include all the semiconductors we have

uncovered to date. The more we will understand why ancient cultures did what they did.They

used the power of time and empiric testing to instinctively know how to best utilize the

photoelectric effect to stay well. The ancestral human diet formed around the East African rift

zone and the conditions of existence that existed at our origin. This Epi-paleo Rx seems to help

the collagen semi conductor in the body and brain, while maximizing the other semiconductors

such as water, to improve its ability to transmit energy using the coherence of water. When these

are maximized, we magically see Vitamin D levels rise without supplementation, DHEA levels

rise, and HS CRP levels fall. This also helps explain to physicians why some of their patients who

they supplement large doses of vitamin D 3, never seem to make a dent in their levels when they

measure their serum after some time with aggressive supplementation. Adding 100 micrograms

of Vitamin K2 with every 1000 IU increase of Vitamin D3 we add while we simultaneously are

improving their semiconductors using the Epi-paleo Rx. This can help repair the semiconductors

quicker when the Epi-Paleo Rx is used simultaneously to improve the other factors important to

quantum biology. When we do it this way we begin to see changes and permanence of the

Vitamin D level 12-18 months in. The duration of change is directly proportional to the quality of

the semi conductor’s ability to transduce energy due to the current disease status. The sicker you

are the longer it will take. This also is based in Einstein’s math built into the photoelectric effect

of light. It is based upon his fourth paper from 1905 on Brownian motion and stochastic calculus.

To gain the benefit of sunlight’s frequency of the wavelength, we need the ability to absorb it. If

our semiconductors are run down for any reason, the power of the sun can alter cellular

signaling to cause disease. This does not mean we should avoid the sun, it means we need to

improve our conditions of existence, to improve our bodies semiconductors’ ability to transmit

the frequency of the spectrum of light, to power our cells. Our body is designed to take the sun’s

natural electro-magnetic radiation, called visible light, and its intrinsic energy package, the

photon, and turn it from an EMF message to a chemical message in our cells to signal and power

life.

When the semiconductors of the body are degraded for any reason, vitamin D levels will always

be low. The reason it is low is not because the sun’s light energy has recently changed. It is

because our semiconductors have been degraded by our epigenetic choices or how we are forced

to live our modern life. Today’s low level of Vitamin D tells you something deeply about the

recommendations “experts” have made for us when you realize the sun’s light has not changed.

It means their recommendations of how we should live have changed our semiconductors. It also

means their beliefs have dramatically altered the choices we have allowed to occur for us and our

families. These beliefs have created environmental mismatches which have acted to subjugate

the rules of nature for a healthy life.

We are the experts of us, and we need to realize this. We need to allow the laws of nature dictate

our health outcomes. This is where the science of quantum mechanics should marry to modern

healthcare. We need to move away from the experts ideas and move back toward how Einstein

says the elements of life should work at a foundational level. We need to allow nature’s design

dictate our choices and not a randomized controlled clinical trial. There is a deep lesson to learn

buried in Einstein’s genius for all life. It is time we all pay attention it to make the difference we

are looking for in medicine.

Lipid Alcohols and Occurrence 

Due to the diversity of synthetic pathways different organisms will contain or excrete different ranges of fatty alcohols.  Most fatty alcohols occur in biota as waxes, esters with fatty acids These compounds can have relatively high carbon contents and  chain lengths up to C64 have been observed. These compounds serve several purposes to the organism that produces them.  In the marine environment these can be summarized

1. Energy reserve
2. Metabolic water reserve
3. Buoyancy generator
4. Biosonar lens in marine mammals.
5. Thermal insulator.

In the terrestrial environment, another range of functions can be ascribed to the waxes from plants

1. Prevention of desiccation
2. Protection from bacterial attack and
3. UV screening.

In birds, waxes are secreted by the uropygial or the preening gland and are used to maintain the condition of the feathers This may be  for waterproofing as well deterring pests

References 

Sargent, J. R. et.al., Hydrobiologia 167: 101-114. 

Sargent, J. R.et.al., Marine Waxes. Chemistry and Biochemistry of Natural Waxes.Amsterdam, Elsevier: 49- 91 

(Dahl, K. A. et.al., Geochimica et Cosmochimica Acta 69(10): 2547-2558)  

(Buckner, J. S, et.al., Comparative Biochemistry and Physiology B-Biochemistry & Molecular Biology 114(2): 207-216. 

Nelson, D. R, et.al., Comparative Biochemistry and Physiology B-Biochemistry & Molecular Biology 123(2): 137-145). 

Jacob,et.al., Chemistry and Biochemistry of Natural Waxes. Amsterdam, Elsevier: 93-146. 

375

376

377

Lipids and Evolution

 Lipid vesicles are connected with the idea that  

compartmentalization is an important principle for  the development of life on Earth since it leads to  the first working cellular unit. 

Deamer DW, Role of lipids in prebiotic structures. BioSystems 1980, 12:167]175.  

Deamer DW: Role of amphiphilic compounds in the evolution of membrane structure on the early Earth. Origins Life 1986,  17:3-25  

Morowitz HJ, Heinz B, Deamer DW: The chemical logic of a minimum protocell. Origins Life 1988, 18:281-287.  Deamer DW: The first livingD systems: a bioenergetic perspective. Microbiol Mol Biol Rev 1997, 61:239-261. 

Evolutionary role of Lipids and Immunity

Many of the receptors that activate the  innate immune system have evolved to  recognize and react to the hydrophobic  portions of molecules should these  

become suddenly exposed. 

NATURE REVIEWS | IMMUNOLOGY VOLUME 4 | JUNE 2004 | 469 379

Evolutionary role of Lipids and Immunity

An evolutionarily ancient alert system is one in  

which 

many of the receptors that activate the innate  

immune system have evolved to recognize and  

react to the hydrophobic portions of molecules  

should these become suddenly exposed. 

NATURE REVIEWS | IMMUNOLOGY VOLUME 4 | JUNE 2004 | 469

What is fascinating most is the intelligence of the system.  It seems our genes have found ways to take notes, to  remind themselves what to do with the various nutrients  they are fed.

Our genes are not written in stone. They are exquisitely  sensitive to how we treat them. Like a fine painting  passed down through generations, conditions that either  harm or preserve are permanently recorded in the  provenance of a family’s DNA. When the DNA is

mistreated, like a Monet thrown into the corner of a damp  musty basement, the inheritance loses its value. And the  losses may be devastating.

Is Metadichol is retraining the forgetful genome in all of us ????

Through mechanisms not fully understood, DNA has been programmed  at some point in the past by epigenetic markers that can turn certain  DNA portions on or off in response to certain nutrients.( METADICHOL IS  ONE OF THEM)

The entire programming system is designed for change; these markers  can, apparently, fall off, causing the genetic brain to forget, at least  temporarily, previously programed information. This forgotten information  can be recalled, given the right environment. This is why we all have the  potential to be—or at least give birth to—genetic lottery winners,  because a forgetful genome can be retrained.

What is fascinating most is the intelligence of the system. It seems our genes have found ways to  take notes, to remind themselves what to do with the various nutrients they are fed. 

Here’s how. Let’s say a gene for building bone is tagged with two epigenetic markers, one that binds to  vitamin D and another that binds to calcium. And let’s say that when vitamin D and calcium are both bound  to their respective markers at the same time, the gene uncoils and can be expressed. If there is no calcium  and no vitamin D, then the gene remains dormant and less bone is built. The epigenetic regulatory tags  are effectively serving as a kind of Post-it note:

When there’s lots of vitamin D and calcium around, make a bunch of the protein encoded right here. When  they do, voilà! You’re building bone! It’s truly an elegant design. Of course, DNA doesn’t “know” what a  given gene actually does. It doesn’t even know what the various nutrients it contacts are good for.

our genes are not written in stone. They are exquisitely sensitive to how we treat them. Like a fine painting  passed down through generations, conditions that either harm or preserve are permanently recorded in the  provenance of a family’s DNA.

When the DNA is mistreated, like a Monet thrown into the corner of a damp musty basement, the  inheritance loses its value. And the losses may be devastating.

Our genes make their day-to-day decisions based on  chemical information they receive from the food we  eat, information encoded in our food and carried from  that food item’s original source, a microenvironment of  land or sea. In that sense, food is less like a fuel and  more like a language conveying information. Synthetic  drugs do not confer any information they carry no  genes in them.

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Lipids and EvolutionBillions of years ago the earth’s atmosphere was reducing one

4H2 + 2CO2 + HSCoA → CH3COSCoA + 3H2O,  ΔG0’ ≈ – 59 kJ/mol

Acetyl-CoA is necessary for the synthesis of amino acids,  carbohydrates, nucleotides and lipids. It serves as a paradigm for  almost all aspect of the molecular secret of ancient pathways

1. M. Flugel, Chirality and Life

Springer Verlag Berlin, Heidelberg 2011

385

Cyanobacteria — one of the largest, oldest and most  

important groups of bacteria on Earth — are already pretty  

much responsible for life as we know it.  

In the Archaean and Proterozoic eons, 2.5 billion years ago,  

cyanobacteria flourished by using light and carbon dioxide  

for nourishment. The oxygen given off by this  

photosynthesis created Earth’s oxygen-rich atmosphere,  

making the evolution of ever more complex life forms  

possible.

386

Biosynthesis of Wax esters and alcohols

Scheme for fatty alcohol and wax production. FAS produces a C16 fatty acid that undergoes  repetitive C2 chain elongation. These may be converted to “free” fatty acids by cleavage of the  CoA.S group. Alternatively, the two step FAR process converts the carboxylic acid group to (i)  

an aldehyde and (ii) an alcohol. In many organisms, the acid and alcohol are combined to  produce a long chain wax. 

387

Metadichol  

can be recycled  

Postulated pathway for interconversion of very long chain fatty alcohols and acids by the enzymes  Reaction 1: alkane 1-mono-oxygenase. 

Reaction 2: fatty alcohol:NAD+ oxido-reductase. 

Reaction 3: fatty aldehyde: NAD+ oxido-reductase. 

Reaction 4: uptake via ABCD1 (the fatty acid transporter, ATP-binding cassette protein D1, which is  also called ALDP).  

 Reaction 5: very long chain fatty acyl CoA ligase. 

In the fatty alcohol cycle, VLCFA are converted to fatty acyl CoA and reduced to fatty aldehyde and  fatty alcohol in NADPH-dependent reactions Net flow of substrates toward oxidation would prevent  accumulation of precursors. 

Experimental Biology and Medicine 229:215-226 (2004) 388

Nutraceuticals and Drugs

Anything biologically derived will hit multiple targets for the simple reason that  billions of years of evolution has made it precisely that way.  

Metadichol hits multiple targets as it has had billions of years of evolution in  its favor.

FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, May 4, 2020

Vitamin C and Coronavirus: Not a
Vaccine; Just a Humble Cure

Commentary by William F. Simmons and Robert G.
Smith, PhD

(OMNS May 4, 2020) During the pneumonia epidemic in North Carolina in the 1940’s, after

American soldiers returned from the war in Europe, a small-town physician used an anti-
infective protocol of intravenous vitamin C to cure 42 cases of viral pneumonia. [1] During the

same period, the physician used a similar treatment to cure 60 cases of viral poliomyelitis. All
patients were clinically well within 72 hours. [2] This seemingly incredible event occurred before
there was a polio vaccine. The doctor was Frederick Robert Klenner of Reidsville, North
Carolina.
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During that same time interval, Klenner used a similar method to cure an assortment of other
maladies, including herpes zoster, herpes simplex, chicken pox, influenza, virus encephalitis,
measles, and mumps. Over the course of his practice, Klenner discovered that vitamin C was not
only anti-viral, but anti-bacterial, anti-fungal, and anti-toxin as well. He also discovered that, in
general, the higher the dose, the more effective the therapy was against the disease, which
resulted in shortening the duration of the anti-infective vitamin C treatment. In his published
papers, Klenner found that intravenous injection was necessary to attain adequately high blood
levels of vitamin C.
Even before Klenner started his medical practice in Reidsville, it was known that a sufficiently
high level of vitamin C was cytotoxic to cancer cells. Several decades later, Linus Pauling and
Ewan Cameron used Klenner’s intravenous therapy to treat a small group of cancer patients, and
found that it increased their survival time. [3,4] Evidently, the high level of vitamin C from their
intravenous protocol was cytotoxic to cancer cells — but spared other cell types. In response, the
Mayo Clinic conducted a much larger, more structured study, supposedly using the same vitamin
C doses as the Cameron/Pauling study, and found the therapy to be ineffective. But there was an
important difference. The Mayo Clinic study used oral doses. Pauling critiqued the study,
pointing out that intravenous administration was necessary. The Mayo Clinic denied access for
Pauling and Cameron to inspect its data. Some years later, the Mayo Clinic conducted yet
another trial, but found the same negative result. Since that time, the wider medical community
has written off the approach of using vitamin C against cancer.
After the passage of several decades, this stand-off was broken when others in the field “realized”
that the Cameron/Pauling trial had used intravenous administration of Vitamin C, while the
Mayo Clinic, although it had used the same dosage of 10 grams per diem, had also consistently
used oral administration of the substance — a fact that Pauling pointed out at the time. [3-5] A
group associated with the National Institutes of Health (NIH) coalesced around the investigation
of the difference between the behavior in the human body of vitamin C given orally and given
intravenously — the so-called “pharmacokinetics” of vitamin C. This group, which includes Mark
Levine and Sebastian Padayatty, has repeatedly affirmed that the blood concentration required
to be cytotoxic to cancer cells requires intravenous or intramuscular administration [6,7] — as
Klenner had maintained as early as the 1940’s.
More recent study of the behavior of vitamin C in the body (its pharmacokinetics) has yielded
many results. The NIH group has confirmed many of the results that Klenner achieved during
his pioneering vitamin C treatments. They have also confirmed that the efficacy of vitamin C in
this cancer treatment is related to generation of hydrogen peroxide, as originally concluded by
Linux Pauling. [8-10] Perhaps most importantly, the study of the pharmacokinetics of vitamin C
has greatly clarified how vitamin C destroys invading organisms, such as viruses, bacteria, and
fungi. [11-12]
Diseased cells tend to accumulate iron. The ascorbate (vitamin C) ion contributes to the
production of hydrogen peroxide. In a reaction called the Fenton Reaction, an iron ion reacts
with a molecule of hydrogen peroxide molecule to produce free radicals (reactive oxygen species,
ROS) that can oxidize and damage any other molecules in their proximity. When this activity
occurs inside the diseased cell, the inner workings of the cell are destroyed, and the cell is
rendered inoperative. [13,14] A similar Fenton reaction mechanism can disable viruses before
they invade a living cell. [15,16] Any cell types, for example some cancers, that lack normal levels

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of the catalase enzyme (that removes hydrogen peroxide) are susceptible. [17]
The important point here is that this anti-viral mechanism has nothing to do with the type of the
target viral particle or its molecular antigens, which is the strategy upon which modern vaccines
depend. If the invading organism mutates, the Fenton reaction process will destroy the cell all
the same — without any need of appropriate antibodies. The diseased cells self-select, since it is
they that are hoarding the iron. The increased availability of ascorbate and hydrogen peroxide
leaves the healthy cells untouched.
The COVID-19 infection has been compared to the flu and severe pneumonia, which can be
successfully treated by high-dose vitamin C treatment. [18-23] Although several ongoing clinical
trials testing an intravenous anti-infective protocol of high-dose vitamin C are still incomplete,
there is no reason to suspect that this protocol would fail since it has succeeded against every
virus it has been set against. [24,25] And, considering the chemical strategy upon which it
depends, one would conclude that success will be likely.
An intravenous anti-infective protocol of vitamin C is not the highly sought-after vaccine which
the pharmaceutical industry is desperate to concoct. Waiting for its development is at the cost of
many lives. But intravenous vitamin C is almost certainly the humble cure we seek, available
now.

The History of a Viral Cure
At the very end of the year of 2019, patients with an unexplained pneumonia appeared in
Wuhan, China. Around a week later, on January 7, 2020, a new coronavirus was detected in a
Wuhan laboratory at 9:00 pm. Three days later, on January 10, the laboratory detected
pathogenic nucleic acids at around 8:00 pm. People in Wuhan continued to succumb to the
coronavirus over the next four weeks, and, by February 4, 20,000 cases of coronavirus had been
identified in China, with 406 dead. [26,27]
On January 20, two weeks prior, South Korea, became one of the first countries to be affected by
coronavirus outside of China. The United States reported its first case on the same day. [26,27]
Sometime between late January and the first days of February, 2020, the Chinese government
placed an order with Dutch State Mines (DSM) for 50 tons of vitamin C. Trucks arrived in
Wuhan, the epicenter of the epidemic, on February 9, 2020. [28] Three days later, on February
12, Zongnan Hospital in Wuhan announced a trial of intravenous vitamin C against Coronavirus.
[24,25] Patients would be administered 24,000 milligrams of vitamin C each day for 7 days. The
next day, on February 13, Dr. Richard Cheng, director of the Medical and Scientific Advisory
Board to the International Intravenous Vitamin C China Epidemic Medical Support Team, and
U.S. board-certified specialist in anti-aging medicine, announced a second intravenous vitamin C
study, in which 6,000 to 12,000 milligrams per day would be given to moderate and severe
cases. Some allowance would be made for the study of oral administration. [25] These
announcements were made on the hospital’s website, and these protocols were being published
all over Asia. But the American news channels did not cover this story. The next day, February
14, the clinical trial commenced at Zhongnan Hospital in Wuhan, China.
In just two days, on February 16, apparently since the results had been so unambiguous,

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Shanghai announced an “official” recommendation to use high-dose intravenous treatment of
vitamin C to treat COVID-19. The official recommendation called for doses ranging from 50-200
milligrams per kilogram of body weight per day, or up to as much as 16,000 milligrams per day.
Four days later, on February 20, Xi’an Jiaotong University Second Hospital reported that 4
patients with severe conoravirus pneumonia had recovered. [29]
The next day, on February 21, Dr. Richard Cheng announced a third intravenous vitamin C trial
targeting coronavirus. [25] Cheng called for immediate use of vitamin C for the prevention of
severe coronavirus infection. He declared that the “current sole focus (in the U.S.) on vaccine
and specific anti-viral drugs is misplaced”. Cheng further stated that 50 tons of vitamin C had
arrived in China about two weeks prior, and was reported in Chinese media, but not in western
media. Cheng further maintained that news of vitamin C research for COVID-19 was being
actively suppressed.
Six days later, on March 1, a report from a hospital in Daegu, South Korea, claimed that
inpatients had been given an infusion of 30,000 mg vitamin C; some got better after 2 days,
most had symptoms disappear after one injection. [30]
Two days after that, on March 3, Dr. Cheng reported an intravenous vitamin C study using
12,000 – 24,000 mg / day, administered to the patient immediately upon arrival at the hospital.
Cheng again claimed that news of vitamin C research for COVID-19 is being actively suppressed,
and that anyone in the West saying that vitamin therapy can stop coronavirus is already being
labeled as “promoting false information”, and promulgating “fake news.” On the same day, the
Government of Shanghai, China announced its official recommendation that COVID-19 should
be treated with high amounts of intravenous vitamin C.
Three days later, on March 6, a medical team from the Second Affiliated Hospital of Xi’an
Jiaotong University in China reported on the successful treatment of coronavirus patients with
vitamin C. In a press release posted on the hospital website, the team described how “… patients
have recovered after being treated with high doses of the vitamin.” The medical team
recommended that “vitamin C treatment should be initiated as soon as possible after admission
to the hospital.” Another hospital, Zhongnan Hospital of Wuhan University, was starting another
study in which they hypothesized that vitamin C infusions can help improve the prognosis of
patients with severe acute respiratory infection (SARI). In yet a further development, the
Shanghai Medical Association in China published a consensus on the treatment of coronavirus
disease. Based on the study of more than 300 clinical patients and developed by 30 experts in
the treatment of new coronavirus pneumonia, it recommended high dose vitamin C for even
light infection with the virus. This recommendation, described as the “Shanghai Plan”, attracted
widespread attention, including on Shanghai television. [31]
Five days later, on March 11, the Japanese published an intravenous vitamin C protocol, and
released an educational video explaining the use of high-dose oral vitamin C (1000 mg 3x daily
to bowel tolerance) along with other essential nutrients to protect against COVID-19. [32] Other
important nutrients to prevent infection were included: vitamin D (2000-5000 IU/d), zinc (20
mg/d), selenium (100mcg/d), and magnesium (400 mg/d, in malate, citrate, or chloride form).
The next day, on March 12, the Government of Shanghai stated that China is now officially
recommending that high amounts of intravenous vitamin C be used to treat the novel

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coronavirus COVID-19. [33] The recommended dosage depends on the severity of the
individual’s illness, but it ranges from 50 to 200 milligrams per kilogram of body weight per day.
That equates roughly to 4,000 to 16,000 milligrams per day in adults.
Meanwhile, the coronavirus was ravaging New York City. On March 24, twelve days after the
Government of Shanghai announced its official recommendation, the New York Post reported
that Northwell Health, New York state’s largest health system, which operates 23 hospitals there,
were treating “seriously sick” coronavirus patients with intravenous vitamin C, and were using it
system wide. [34] Dr. Andrew Weber, a pulmonologist and critical-care specialist at the hospital,
said that the treatments were started based on work done with coronavirus patients in Shanghai,
China. Patients entering these New York hospitals were given doses of 1500 milligrams of
vitamin C immediately, with two or three recurring doses totaling 300 to 6000 mg/day. The
patients receiving vitamin C did significantly better than those who did not get vitamin C,
according to Dr. Weber. Weber said that vitamin C helps the body fight off an inflammatory
overreaction to the infection which occurs as a result of coronavirus, a condition called sepsis.
Pulmonologist Weber said that vitamin C levels in coronavirus patients drop dramatically when
sepsis develops. “It makes all the sense in the world to try to maintain this level of vitamin C”,
said Weber. Jason Molinet, a spokesman with Northwell Health confirmed for the New York
Post that vitamin C treatments for coronavirus patients are being “widely used” across the
hospital system.
In Seattle, emergency physician Dr. Ryan Padgett contracted COVID-19 with severe pneumonia
and was saved over several days in the period March 12-23 by the application of high-dose
intravenous vitamin C along with a drug approved to treat cancer, both for the purpose of
blocking the life-threatening “cytokine storm” in the lungs. [35] And in Richmond, Virginia, Dr.
Jeff Brown also contracted COVID-19 with severe pneumonia, was given hydroxychloroquine,
which didn’t help, and was finally saved by the same combination of cancer drug and high-dose
intravenous vitamin C. [36,37] In Houston, Texas, an experimental combination of intravenous
high-dose vitamin C and drug treatment for patients with COVID-19 with severe pneumonia has
been working exceptionally well. Dr Joseph Varon said, “To date, we have 0% mortality at United
Memorial Medical Center. Zero percent. I know it’s too good for people to believe in this but it’s
working.” [38]
Moreover, a group of critical-care doctors widely spread across the United States has set up a
website that provides an explanation, a press release, and a protocol for the treatment that they
have used to effectively prevent patients with severe COVID-19 pneumonia from needing a
ventilator and from death. [39] They implore doctors to use the protocol or a similar one on
COVID-19 patients at the earliest opportunity after admission to save lives. [40]
In the meantime, on April 8, approximately 100 days since the unexplained pneumonia
appeared in Wuhan, the lockdown in China is now being lifted. [27]
Yet, in spite of the overwhelming evidence of the efficacy of an intravenous vitamin C protocol
against coronavirus, the FDA, the CDC, and many respected members of the medical community
inexplicably jeopardize their own credibility, apparently, to save the irrelevant business model of
the pharmaceutical industry. The respect will be hard to win back. And that is right and proper.

(Texas resident William F. Simmons studied Greek, Hebrew and Arabic at universities in his

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home state, as well as in Jerusalem and Amman, Jordan. He read A Physician’s Handbook on
Orthomolecular Medicine in 1982, and has been keenly interested in the topic ever since. Robert
G. Smith is a physiologist and Associate Research Professor at the University of Pennsylvania’s
Perelman School of Medicine. Dr. Smith is the author of The Vitamin Cure for Arthritis and also
The Vitamin Cure for Eye Disease.)

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Stuart Lindsey, Pharm.D. (USA)
Victor A. Marcial-Vega, M.D. (Puerto Rico)
Charles C. Mary, Jr., M.D. (USA)
Mignonne Mary, M.D. (USA)
Jun Matsuyama, M.D., Ph.D. (Japan)
Joseph Mercola, D.O. (USA)
Jorge R. Miranda-Massari, Pharm.D. (Puerto Rico)
Karin Munsterhjelm-Ahumada, M.D. (Finland)
Tahar Naili, M.D. (Algeria)
W. Todd Penberthy, Ph.D. (USA)
Dag Viljen Poleszynski, Ph.D. (Norway)
Selvam Rengasamy, MBBS, FRCOG (Malaysia)
Jeffrey A. Ruterbusch, D.O. (USA)
Gert E. Schuitemaker, Ph.D. (Netherlands)
T.E. Gabriel Stewart, M.B.B.CH. (Ireland)
Hyoungjoo Shin, M.D. (South Korea)
Thomas L. Taxman, M.D. (USA)
Jagan Nathan Vamanan, M.D. (India)
Garry Vickar, MD (USA)
Ken Walker, M.D. (Canada)
Raymond Yuen, MBBS, MMed (Singapore)
Anne Zauderer, D.C. (USA)

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Fauci: Early COVID-19 vaccines will only prevent symptoms, not block the virus

The latter goal is a secondary endpoint, according to Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.

“The primary thing you want to do is that if people get infected, prevent them from getting sick, and if you prevent them from getting sick, you will ultimately prevent them from getting seriously ill,” Fauci said at Yahoo Finance’s All Markets Summit Monday.

“What I would settle for, and all of my colleagues would settle for, is the primary endpoint to prevent clinically recognizable disease,” he said.

That level of protection would be the ultimate goal to diffusing the crisis, but is hard to do with companies facing an immediate demand for some sort of solution. While no vaccine is 100% effective, having a majority of the population inoculated and higher percentages of efficacy is the best to hope for. The most effective vaccine is the measles vaccine, which elicits an antibody response 98% of the time.

Currently AstraZeneca (AZN), developing Oxford University’s vaccine; Pfizer (PFE) with partner BioNTech (BNTX); Moderna (MRNA); and Johnson & Johnson (JNJ) are all in-late stage trials. Among them, Pfizer and BioNTech are in the lead to provide a first look at the vaccine’s effectiveness in the second half of November. At best, the duo could be the first to receive emergency use authorization and the only ones to do so by the end of the year.

But there are still other vaccine candidates in the pipeline — many in early or pre-clinical stages. If their slower trajectory puts them in a situation of testing the vaccine when the outbreak lessens, it could make it harder to test the potential effectiveness of a candidate.

For this reason, the U.K. is looking at challenge trials, which intentionally infect a smaller group of participants with the virus in an effort to test a vaccine’s or treatment’s efficacy.

Fauci said the U.S. is not anticipating such a move because the rate of spread is so high in the country that it’s sufficient enough of an environment to test the vaccine. The daily case count for the U.S. in the past few days has reached a new record of more than 80,000 cases.

“So although you can get some good information from a challenge trial, the real-world information that you want is out in the field when someone is actually being exposed to natural infection, and to determine if the vaccine prevents against that,” Fauci said.

“So right now we’re not planning any challenge studies because we have so much infection going on.”

Pamphlet version 2- Global Health Now & How

This gift of life to humanity and the plant ,animal and the friendly bacteria and viruses even allows the non friendly agents to play a minor role to train others to live long and strong.

The animation story of your way to health glory shares how nanosoma will optimize the entire supply chain of global health quality for all those who are receptive to its gentle invitation to the greater cellebration of health beyond our conditioning to see life as inevitable conflict, disappointment and unnecessary drama.

The keys to your worlds health are described by the nanosoma discoverer on the 12/14/2021 interview by Erai and kylea beckmann on their milestone global health goes viral,next step in human evolution,free speech and choice global town hall media;archived on consciousvitality.com.

Metadichol, the active ingredient of Nanosoma and patented nanomolecule form of policosanol, also he broad antiviral properties. Independent testing demonstrates that Metadichol, Nanosoma’s active ingredient, inhibits the SARS-CoV-2 virus and other ‘enveloped’ pathogens. The plant-based emulsion disrupts 17 deadly pathogens including Dengue, Malaria, H1N1, and Ebola, according to independent testing.

The Federal Drug Administration (FDA) recognizes Nanosoma as Generally Regarded As Safe (GRAS). The ingredients include policosanol (from sugar cane), certifiably pure water, as well as Vitamin E. The Swiss manufacturing site of the active ingredient, Metadichol, is certified by the FDA.

Nanosoma’s Certificate of Analysis toxicology report states that a person would have to drink 300 bottles of Nanosoma per day to get an adverse reaction.

All testing of Metadichol is independent and peer-reviewed.

• Get 15-30 minutes of sun with 60% of your body exposed,even if it’s through a window. more melanated folks need 1 hour.

• Adults need 6-12 glasses daily of non tap water

• Eat more plant based protein like rice and beans.peanuts,almonds and yogurt.

• Eat more uncooked plant foods,apples,bananas,berries

• Have less denatured sugar,more raw cane sugar,uncooked honey,stevia.

Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19

A 47-year-old woman from Wuhan, Hubei province, China, presented to an emergency department in Melbourne, Australia. Her symptoms commenced 4 d earlier with lethargy, sore throat, dry cough, pleuritic chest pain, mild dyspnea and subjective fevers (Fig. 1a). She traveled from Wuhan to Australia 11 d before presentation. She had no contact with the Huanan seafood market or with known COVID-19 cases. She was otherwise healthy and was a non-smoker taking no medications. Clinical examination revealed a temperature of 38.5 °C, a pulse rate of 120 beats per minute, a blood pressure of 140/80 mm Hg, a respiratory rate of 22 breaths per minute, and oxygen saturation 98% while breathing ambient air. Lung auscultation revealed bi-basal rhonchi. At presentation on day 4, SARS-CoV-2 was detected in a nasopharyngeal swab specimen by real-time reverse-transcriptase PCR. SARS-CoV-2 was again detected at days 5–6 in nasopharyngeal, sputum and fecal samples, but was undetectable from day 7 (Fig. 1a). Blood C-reactive protein was elevated at 83.2, with normal counts of lymphocytes (4.3 × 10⁹ cells per liter (range, 4.0 × 10⁹ to 12.0 × 10⁹ cells per liter)) and neutrophils (6.3 × 10⁹ cells per liter (range, 2.0 × 10⁹ to 8.0 × 10⁹ × 10⁹ cells per liter)). No other respiratory pathogens were detected. Her management was intravenous fluid rehydration without supplemental oxygenation. No antibiotics, steroids or antiviral agents were administered. Chest radiography demonstrated bi-basal infiltrates at day 5 that cleared on day 10 (Fig. 1b). She was discharged to home isolation on day 11. Her symptoms resolved completely by day 13, and she remained well at day 20, with progressive increases in plasma SARS-CoV-2-binding IgM and IgG antibodies from day 7 until day 20 (Fig. 1c and Extended Data Fig. 1). The patient was enrolled through the Sentinel Travelers Research Preparedness Platform for Emerging Infectious Diseases novel coronavirus substudy (SETREP-ID-coV) and provided written informed consent before the study. Patient care and research were conducted in compliance with the Case Report guidelines and the Declaration of Helsinki. Experiments were performed with ethics approvals HREC/17/MH/53, HREC/15/MonH/64/2016.196 and UoM#1442952.1/#1443389.4.

a, Timeline of COVID-19, showing detection of SARS-CoV-2 in sputum, nasopharyngeal aspirates and feces but not urine, rectal swab or whole blood. SARS-CoV-2 was quantified by rRT-PCR; cycle threshold (Ct) is shown. A higher Ct value means lower viral load. Dashed horizontal line indicates limit of detection (LOD) threshold (Ct = 45). Open circles, undetectable SARS-CoV-2. b, Anteroposterior chest radiographs on days 5 and 10 following symptom onset, showing radiological improvement from hospital admission to discharge. c, Immunofluorescence antibody staining, repeated twice in duplicate, for detection of IgG and IgM bound to SARS-CoV-2-infected Vero cells, assessed with plasma (diluted 1:20) obtained at days 7–9 and 20 following symptom onset. d–f, Frequency (left set of plots) of CD27^hiCD38^hi ASCs (gated on CD3^–CD19⁺ lymphocytes) and activated ICOS⁺PD-1⁺ T_FH cells (gated on CD4⁺CXCR5⁺ lymphocytes) (d), activated CD38⁺HLA-DR⁺ CD8⁺ or CD4⁺ T cells (e), and CD14⁺CD16⁺monocytes and activated HLA-DR⁺ natural killer (NK) cells (gated on CD3^–CD14^–CD56⁺ cells) (f), detected by flow cytometry of blood collected at days 7–9 and 20 following symptom onset in the patient and in healthy donors (n = 5; median with interquartile range); gating examples at right. Bottom right histograms and line graphs, staining of granzyme A (GZMA (A)), granzyme B (GZMB (B)), granzyme K (GZMK (K)), granzyme M (GZMM (M)) and perforin (Prf) in parent CD8⁺ and CD4⁺ T cells and activated CD38⁺HLA-DR⁺ CD8⁺ and CD4⁺ T cells. Gating and experimental details are in Extended Data Fig. 3.

Full size image

The secret agents that warn a threatened cell

Mitochondria, best known as the cell’s power plants, live a double life.

09 December 2019

Cell biology

In cells under attack, mitochondria can act as sentinels, revving up the repair apparatus deep inside the nucleus to protect the cell’s primary genetic cargo.

Mitochondria, the cell’s energy-making structures, contain DNA distinct from that in the nucleus. To explore how mitochondria communicate with the nucleus, Gerald Shadel at the Salk Institute for Biological Studies in La Jolla, California, and his colleagues dosed cells with the cancer drug doxorubicin, which damages DNA. The cells’ mitochondrial DNA alerted the nuclear DNA, which activated a repair protocol.

The team altered melanoma cells to prompt their mitochondria to release more DNA. When these cells were implanted into mice, they produced tumours that survived doxorubicin treatment better than standard melanoma tumours.

The scientists also put the mitochondria of engineered mice on alert and dosed these mice with ionizing radiation, which is another cancer treatment. The engineered mice showed signs of more vigorous nuclear repair in their spleens than control mice.

The results show that when damaged by a toxin or other form of abuse, the abundant mitochondrial DNA warns the nucleus that an attack is underway. This surveillance system might explain how cells acquire resistance to some DNA-targeting cancer drugs.

Targeting Orphan Nuclear Receptors for Treatment of Metabolic Diseases and Autoimmunity

Thomas P. Burris, Scott A. Busby, and Patrick R. Griffin

Abstract

The nuclear receptor (NR) superfamily is composed of 48 members in humans and includes receptors for steroid hormones, thyroid hormone, various lipids and oxysterols. This superfamily has been a rich source of drug targets for myriad diseases including inflammation, cancer, and metabolic disorders. Approximately half of the superfamily have well characterized natural ligands while the remaining receptors are considered orphan receptors and remain a focus of a number of investigators assessing their ability to be regulated by ligands. Here, we review recent discoveries that yield important insight into the druggability of three orphan nuclear receptors: the retinoic acid receptor-like orphan receptors (RORs), peroxisome proliferator-activated receptor γ (PPARγ), and liver receptor homologue-1 (LRH-1).

The nuclear receptor (NR) superfamily is composed of 48 members in humans and includes receptors for steroid hormones, thyroid hormone, various lipids and oxysterols. NRs function as ligand-dependent transcription factors and are share a modular domain structure (Fig. 1) (Mangelsdorf, et al., 1995). A general characteristic of members of the superfamily is a highly conserved DNA binding domain (DBD) also called a C region. Amino-terminal to the C region is the A/B region and is highly variable among superfamily members. This domain, depending on the receptor, may contain ligand-independent transcriptional activation activity. The second most conserved region is carboxy-terminal to the DBD is the ligand binding domain (LBD) or E region. This domain is responsible for recognition and binding of the receptor’s ligand as well as ligand-dependent transcriptional activity. A relatively short region connects the C region to the E region (region D) and is known as the hinge domain. Some receptors also contain a region carboxy-terminal to the ligand binding domain known as the F region.

Figure 1

Structural domain organization of nuclear receptors. Regions (A/B, C, D, E, and F) are indicated above the schematic and domains are indicated below the schematic. AF=Activation function, DBD=DNA binding domain, LBD=Ligand binding domain.

Approximately half of the superfamily have well characterized natural ligands while the remaining receptors are considered orphan receptors and remain a focus of a number of investigators assessing their ability to be regulated by ligands (Kliewer, et al., 1999; Mangelsdorf and Evans, 1995). The vast majority of receptors that have identified natural ligands are also validated targets for clinical drugs. This superfamily has been a rich source of drug targets for myriad diseases including inflammation, cancer, and metabolic disorders. Thus, there remains significant interest in identification of ligands that regulate orphan members of the NR superfamily due to their potential for utilization as potential drugs to treat human disease.

Over the past 2 years, there have been significant breakthroughs in the identification of novel ligands for several orphan NRs and in this review we examine the progress that has been made toward identification of ligands for retinoic acid receptor-related orphan receptors (RORs) and the liver receptor homologue 1 (LRH1) as well as a novel class of ligand for peroxisome proliferator-activated receptor γ (PPARγ) that holds promise for an improved pharmacological profile over older glitazone agonists.

Pharmacological Targeting of Retinoic Acid Receptor-Related Orphan Receptors (RORs) for Autoimmune Diseases

As the canonical domain structure and conserved sequence of members of the NR superfamily became apparent in the 1980s, several laboratories isolated additional members of this superfamily that had no identified ligands. The first member of the ROR subfamily of receptors (RORα) was based on sequence similarities to the retinoic acid receptor (RAR) and the retinoid X receptor (RAR) yielding the name “retinoic acid related-related orphan receptor” (Beckerandre, et al., 1993; Giguere, et al., 1994). Similar receptors, RORβ and RORγ, were identified shortly after RORα was identified (Carlberg, et al., 1994; Hirose, et al., 1994). RORα, RORβ and RORγ display significant sequence similarities and each ROR gene generates multiple isoforms based on alternative promoter usage and splicing. All of the isoforms vary only in the amino-terminal A/B regions of the receptors. RORα, RORβand RORγ display distinct patterns of expression. RORα is widely expressed and is found in the liver, skeletal muscle, skin, lungs, adipose tissue, kidney, thymus and brain (Hamilton, et al., 1996; Steinmayr, et al., 1998). RORβ displays a very restricted pattern of expression and is limited to the central nervous system (Andre, et al., 1998; Andre, et al., 1998). RORγ is most highly expressed in immune tissues including the thymus, but significant expression is also found in the liver, skeletal muscle, adipose tissue and kidney (Medvedev, et al., 1996). RORγt, is exclusively expressed in key cells within the immune system (Miller and Weinmann, 2009). When bound to their specific DNA response elements within the promoter of a target gene, all three RORs constitutively recruit coactivators resulting in activation of transcription of their target genes. Interestingly, another group of orphan nuclear receptors, REV-ERBs, recognize the same response elements as the RORs and are coexpressed in many tissues (Duez and Staels, 2009; Solt, et al., 2011; Yin, et al., 2010). REV-ERBs are ligand-dependent transcriptional repressors and in many cases, functionally antagonize the action of the RORs (Burris, 2008; Raghuram, et al., 2007; Yin, et al., 2007).

Distinct adaptive immune responses directed towards protection against various classes of pathogens are facilitated by differentiation of CD4⁺ T cells into specific types of effector T cells (T_H1, T_H2, and T_H17 cells). RORα and RORγ have garnered significant attention over the past several years due to their essential role in development of T_H17 cells. Prior to the discovery of T_H17 cells, T_H1 cells were considered the effector T cell type responsible for the pathology of autoimmune diseases including psoriasis, multiple sclerosis (MS), and rheumatoid arthritis among others. Key experiments in interferon γ receptor-deficient mice suggested that this may not be the case since since these mice, deficient in T_H1-IFNγ signaling, were actually more susceptible to autoimmune disease (experimental autoimmune encephalomyelitis (EAE) – an animal model of MS) rather than less susceptible to disease (Ferber, et al., 1996; Willenborg, et al., 1996). These data suggested that there may be another, as of yet unidentified, cell type responsible for at least a portion of the autoimmune pathology associated with EAE. Later studies demonstrated that the IL23/IL17 cytokine axis was crucial for autoimmune disease progression in the EAE and collagen induced arthritis (CIA) models and progression was independent of the T_H1 and T_H2 cells (Cua, et al., 2003; Murphy, et al., 2003; Zhang, et al., 2003). Indeed, a distinct lineage of T effector cells that produce IL17 (T_H17 cells) was soon identified (Harrington, et al., 2005; Park, et al., 2005). T_H17 cells have since become recognized as critical mediators of autoimmune pathology (Bettelli, et al., 2008; Littman and Rudensky, 2010). Thus, it became apparent that one might be able to modulate autoimmune disease progression by regulation of T_H17 cell development.

One key factor in development of the T_H17 cells has been shown to be expression of RORs. RORγt was demonstrated to play a critical role in development of T_H17 cells since overexpression of RORγt in naïve CD4⁺ T cells resulted in induction of development of IL17 producing T_H17 cells and RORγt-deficient mice display impaired T_H17 cell differentiation (Ivanov, et al., 2006). The transcriptional cascade leading to T_H17 differentiation is complex and additional transcription factors involved in metabolic regulation such as HIF-1 and RORα have also been demonstrated to play an important role (Dang, et al., 2011; Yang, et al., 2008). Mice deficient in either RORγ or RORα or both receptors displayed resistance to development of autoimmunity (Ivanov, et al., 2006; Yang, et al., 2008) suggesting that one mechanism to reduce autoimmune pathology may be to inhibit these receptors leading to decreased T_H17 cell differentiation. At the time of these discoveries, ligands had not been identified for either of these receptors but developments in 2010 suggested that both RORα and RORγ were indeed “druggable”.

Crystallographic studies of RORα suggested that a sterol such as cholesterol or cholesterol sulfate may function as a natural ligand of this receptor (Kallen, et al., 2004; Kallen, et al., 2002). We later found that hydroxycholesterols were high affinity ligands for both RORα and RORγ and that some of these such as 7-oxygenated sterols (Fig. 2) functioned as inverse agonists suppressing the constitutive activity of both of these receptors (Wang, et al., 2010; Wang, et al., 2010). The structure of the RORγ LBD bound to several oxysterols provided a clear structural basis for these sterols as natural ROR ligands (Jin, et al., 2010). A key breakthrough with this discovery was the ability to develop a radioligand binding assay for RORα and RORγ using high affinity radiolabeled oxysterols and this allowed our group to identify the first synthetic ligands for these two “orphan” receptors. The characterized liver X receptor (LXR) agonist, T0901317 (T1317) was identified as an inverse agonist for both RORα and RORγ and shown to directly bind to the LBD’s of these receptors and inhibit coactivator binding leading to suppression of their constitutive transcriptional activity (Kumar, et al., 2010). T1317 displays promiscuous activity at several NRs including LXR, farnesoid X receptor, pregnane X receptor, and RORα and RORγ limiting its ability to be used as a chemical tool to probe the utility of a selective RORα/RORγ inverse agonist in models of T_H17 cell differentiation; however, a focused medicinal chemistry effort was able to develop a analogue of T1317 (SR1001) that retained activity at both RORα and RORγ but lacked activity at any other NR (Solt, et al., 2011).

Figure 2

Chemical structure of several ROR ligands including sterol derivatives (cholesterol, cholesterol sulfate, 7α-hydroxycholesterol, ursolic acid, and digoxin as well as its derivatives) and non-steroidal compounds such as T0901317 and SR1001.

Unlike the natural ligands that have been identified, SR1001 does not contain a sterol or steroid-like structure (Fig. 2). We were able to demonstrate that SR1001 directly binds to the LBD’s of RORα and RORγ (K_i=111 to 172 nM) leading to a conformational change resulting in loss of affinity for the receptors for coactivator (SRC-2) and increased affinity for corepressor (NCoR) (Solt, et al., 2011). SR1001 effectively suppressed IL17 expression and T_H17 cell development without affecting other T cell lineages (Solt, et al., 2011). Most importantly, SR1001 was effective in delaying the onset and severity of EAE in mice demonstrating proof-of-principle that a small molecule inhibitor of ROR transcriptional activity is effective in suppressing autoimmunity (Solt, et al., 2011).

Littman’s group also identified a small molecule inhibitor of RORγ and this compound was the well-known cardiac glycoside, digoxin (Huh, et al., 2011) (Fig. 2). Digoxin is used clinically for treatment of atrial fibrillation where it directly alters electrical conduction in the heart targeting the Na⁺/K⁺-ATPase. Digoxin displayed a potency (IC₅₀) of ~2 µM for suppression of RORγ-mediated activity (Huh, et al., 2011). Digoxin displayed RORγ specificity and did not affect RORα, DHR3, DAF-12, or the androgen receptor (Huh, et al., 2011). Similar to SR1001, digoxin inhibited T_H17 cell differentiation and delayed the onset and severity of EAE in mice (Huh, et al., 2011). One significant issue of digoxin is the toxicity associated with this drug and the small therapeutic window. These authors examined analogues of digoxin and demonstrated that these compounds also demonstrate activity against RORγ and T_H17 cell differentiation and that the anti-T_H17 cell activity does not correlate with the cardiac glycoside activity suggesting that there may be opportunities for optimization of the RORγ activity with removal of the potential cardiac toxicity (Huh, et al., 2011). A crystal structure of the RORγ LBD bound to digoxin demonstrating the molecular mechanism of inhibition of coactivator binding was reported soon after the original study identifying dixogen as a RORγ inhibitor (Fujita-Sato, et al., 2011). Given the severity of the toxicity associated with and the limited intellectual property space associated with this chemical scaffold, it is unlikely that this would be pursued by pharmaceutical companies even though Huh et al indicate that some digoxin derivatives (Fig. 2) do display RORγ inhibitory activity at levels where they do not display cellular toxicity. However, of critical importance is the fact that these data demonstrate the feasibility of targeting RORγ with small molecule inhibitors for treatment of autoimmune disorders.

Ursolic acid has also been recently shown to inhibit T_H17 cell differentiation via targeting RORγ (Xu, et al., 2011) (Fig. 2). Ursolic acid also delayed the onset and decreased the severity of EAE in mice (Xu, et al., 2011). Ursolic acid, like digoxin, displays a steroid-like chemical structure and, in fact, several have reported that ursolic acid modulates the activity of the glucocorticoid receptor (GR) (Cha, et al., 1998; Kassi, et al., 2009). Biochemical assays indicate that ursolic acid effectively bindings to the RORγ LBD and blocks coactivator binding, but was considerably less active on RORα (Xu, et al., 2011). The possibility that ursolic acid exhibits activity at the GR complicates the interpretation of the results since glucocorticoids are very effective in the EAE model.

Given the validated results in the development of small molecule ligands for RORα and RORγ by multiple teams it is clear that these orphan receptors are druggable. The data also clearly indicate that these compounds have efficacy in suppression of T_H17 cell development and an in vivo model of autoimmunity (EAE model). Thus, targeting the RORs represents a very promising path forward for novel treatments for autoimmunity that offers potential significant advantages over current therapies that broadly target the immune system and/or are typically biologics that must be injected.

Revival of PPARγ Ligands for Type 2 Diabetes

The incidence of diabetes is increasing rapidly as the percentage of the population ages and becomes more obese. According to the National Center for Health Statistics diabetes is now the sixth leading cause of death in the US. Adipose tissue is at the center of the metabolic syndrome, which encompasses an array of medical disorders including insulin resistance and diabetes. Excessive body fat defines obesity and leads to insulin resistance, dyslipidemia, type 2 diabetes (T2D), and cardiovascular disease. Understanding the molecular pathways that link adipose tissue biology to these pathologies is of critical scientific and medical importance. Adipose tissue secretes a variety of cytokines and cytokine-like molecules, called adipokines, which have both positive and negative effects on peripheral insulin sensitivity (Kershaw and Flier, 2004). In obesity, TNFα, IL-1 and resistin are secreted from adipose tissues and suppress insulin action on peripheral tissues (Hotamisligil, et al., 1993; Lagathu, et al., 2006; Steppan, et al., 2001). Conversely, adipose tissues from lean individuals secrete higher levels of adiponectin, a circulating protein that has insulin-sensitizing effects on liver and other tissues (Berg, et al., 2001; Hu, et al., 1996; Yamauchi, et al., 2006).

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is viewed as a master regulator of fat cell biology and differentiation, being both necessary and sufficient to drive conversion of fibroblastic precursors into fat cells (Morrison and Farmer, 2000; Tontonoz, et al., 1994; Willson, et al., 2001). Transcription factors such as C/EBPs and EBF proteins regulate the expression of PPARγ (Jimenez, et al., 2007; Wu, et al., 1996). The glitazones or thiazolidinedione (TZDs) class of drugs which include rosiglitazone and pioglitazone are synthetic ligands that demonstrate high affinity binding to PPARγ (~100nM K_d) and these compounds function as full agonists of the receptor (Day, 1999; Reginato and Lazar, 1999) (Fig. 3). Treatment of animal models of diabetes and diabetic patients with TZDs results in potent insulin-sensitizing activity (Lehmann, et al., 1995) concomitant with decreased expression of insulin resistance-inducing adipokines including TNF-a, IL-1 and resistin, and increased production of the insulin-sensitizing hormone, adiponectin (Sharma and Staels, 2007; Trujillo and Scherer, 2006). Unfortunately, PPARγ agonists can have long-term adverse effects on the health of certain patients, such as increased body weight, fluid retention, and increased risk of heart failure (Lipscombe, et al., 2007). This is unfortunate, as TZDs have consistently shown robust efficacy for treatment of T2D. More recently concerns have increased on the association of TZD use with bone loss (Schwartz, et al., 2006; Wei, et al., 2010). The latter risk is troublesome as detection is typically only made when a patient suffers a fracture. The biguanide metformin is now the first-line medication used for treatment of T2DM as safety concerns over the use of TZDs has grown.

Figure 3

A. Chemical structure of various PPARγ agonists, partial agonists, and “non-agonists”. B. The desired profile of a PPARγ modulator is high affinity binding with minimal to no classical agonism and potent blockage of S273 …

Interestingly, studies in preclinical models and in clinical trials have shown that weight gain and plasma volume expansion can be minimized without loss of insulin sensitization by the use of modulators that are weak or partial agonists of PPARγ. Partial agonists have been referred to as selective PPARγ modulators or SPPARγMs and this class of ligand has been shown to have a different binding mode in the PPARγ ligand binding pocket (LBP) as compared to the full agonists (Berger, et al., 2005). Selective recruitment of transcriptional coactivators by partial agonists has also been demonstrated. A combination of different ligand binding mode and distinct coactivator recruitment profile may explain the change in gene expression patterns compared to that of full agonists (Berger, et al., 2003). These findings highlight that several important aspects of PPARγ action remain unclear. First, there is no general deficiency in PPARγ function in obesity or insulin-resistant states. Hence, it is not clear why synthetic activation of a receptor should afford anti-diabetic effects. Second, while anti-diabetic potency of the PPARγ ligand drugs correlates very well with their binding affinities (Willson, et al., 1996), some ligands with full agonist action, like rosiglitazone, have powerful insulin-sensitizing actions, while other compounds with poor agonist activities, such as the benzyl indole MRL24, retain very good anti-diabetic effects (Acton, et al., 2005).

A recent study by Choi et al demonstrated that many PPARγ-based drugs can activate the receptor by recruitment of co-activators but these compounds have a separate biochemical activity involving blocking the obesity-linked phosphorylation of PPARγ by Cdk5 on S273 of the receptor (Choi, et al., 2010). In this study it was shown that the insulin sensitization efficacy of a rosiglitazone and the partial agonist MRL24 correlates with their ability to block S273 phosphorylation. While it is likely that other kinases can phosphorylate PPARγ on S273, this study demonstrates that activation of CDK5 by pro-inflammatory cytokines leads to an increase of phosphorylation of S273 in cellular models and increased S273-P was observed in obese diabetic mice (Choi, et al., 2010). The level of S273-P correlates with the repression of a subset of PPARγ target genes that are dysregulated in obesity and associated with insulin resistance (Choi, et al., 2010) and interestingly, a recent study indicates that deletion of NCoR in adipocytes facilitates S273 phosphorylation by CDK5 and mimics the action of the TZD treatment. These studies suggested the possibility that the mechanism driving efficacy of PPARγ drugs can be separated from classical activation of the receptor, which if not required for efficacy likely contributes to the adverse event profile of TZDs.

Efforts to discover high affinity PPARγ ligands that lacked classical activation of the receptor while retaining the ability to block S273 phosphorylation in cultured adipocytes and in diabetic mice led to the discovery of SR1664 (Fig. 2.). SR1664 has similar binding affinity as rosiglitazone for PPARγ in a lanthascreen ligand displacement assay (Ki~160nM). In a well established cell-based co-transfection promoter/reporter assay, rosiglitazone induces significant transcriptional activation of the reporter whereas SR1664 failed to transcriptionally activate the reporter even at the highest concentrations tested. On purified PPARγ, both rosiglitazone and SR1664 demonstrated dose-dependent inhibition of the CDK5-dependent phosphorylation of S273. The blockage of phosphorylation of S273 is a direct action of the ligands that requires binding to the LBD of the receptor to induce a conformational change that interferes with the ability of Cdk5 to phosphorylate serine 273. Adipogenesis was the first known biological function of PPARγ and PPARγ agonists have been shown to potently stimulate the differentiation of pre-adipose cell lines (e.g., 3T3-L1 cells). In this study, rosiglitazone potently stimulated fat cell differentiation, where in contrast, SR1664 did not stimulate increased lipid accumulation or changes in morphology characteristic of differentiating fat cells. More importantly, glucose tolerance tests were markedly improved with both rosiglitazone and SR1664. While SR1664 demonstrated potent anti-diabetic activity in diabetic mice there was no measurable increase in fluid retention or weight gain. Not surprising, significant plasma volume expansion and weight gain was observed in the rosiglitazone treated animals. Unlike rosiglitazone, SR1664 did not interfere with bone formation in cultured cells.

These data illustrate that it is possible to develop a new class of anti-diabetes drugs that allosterically block the phosphorylation of PPARγ at S273. Even though SR1664 is only a proof of concept compound that needs to be optimized for improved pharmaceutical properties, these studies represent a significant advancement towards developing insulin sensitizers with improved therapeutic index. Several questions need to be addressed to facilitate development of compounds like SR1664. First, what is the mechanism by which phosphorylation of S273 represses the transcriptional output of a subset of genes that are dysregulated in obesity? Second, what are the molecular and structural determinants that facilitate high affinity binding to PPARγ without inducing classical activation yet maintaining potent blockage of phosphorylation of S273? And third, will non-activating/S273 phosphorylation blockers like SR1664 completely dissociate efficacy from the major side effects associated with TZDs? While the answer to the last question will require testing compounds in man, it seems highly plausible that, as shown in Figure 3, that the therapeutic index will improve as agonism if removed while maintaining blockage of S273 phosphorylation.

Synthetic agonists for LRH-1 for Treatment of Diabetes and Metabolic Diseases

Liver receptor homolog-1 (LRH-1) is a member of the NR5A family of nuclear receptors that also includes the close homolog, steroidogenic factor-1 (SF-1). Although these receptors are considered orphan receptors, a number of reports have identified the presence of bacterial phospholipids in the binding pockets of both SF-1 and LRH-1, but it remains to be determined whether these represent merely structural or fortuitous ligands or if they can modulate receptor activity (Krylova, et al., 2005; Li, et al., 2005; Ortlund, et al., 2005). LRH-1 plays important roles in embryonic development and is highly expressed in the intestine liver, pancreas and ovary (Lee and Moore, 2008). In addition, it is well established that LRH-1 regulates critical enzymes involved in cholesterol homeostasis and bile-acid biosynthesis in the liver in addition to regulating the expression of aromatase in the breast and ovaries (Lee, et al., 2008; Santen, et al., 2009).

A report published recently in Nature by Lee and coworkers identified two unusual phosphatidylcholine (PC) species as LRH-1 agonists that also uncovered a previously unknown role for LRH-1 in the control of glucose homeostasis and insulin sensitivity (Lee, et al., 2011). Dilauroyl PC (DLPC; C12:0/C12:0) and diundecanoyl PC (DUPC; C11:0/C11:0) were shown to function as direct ligands of LRH-1 and modulate the receptor’s activity (Fig. 4). Both phospholipids were able to induce activation of LRH-1 specific promoters such as Shp and Oct4 while closely related phospholipids such as dipalmitoyl PC (DPPC; C16:0/C16:0) did not. In addition, the authors demonstrate that these phospholipids were specific to NR5A family members and did not cross react with other families of nuclear receptors such as PPARα. Mammalian two-hybrid assays confirmed the ability of these two phospholipids to bind to LRH-1 and selectively recruit important coactivators such as SRC-3. Moreover, coactivator peptide association assays with purified LRH-1 suggested that the binding of DLPC to LRH-1 is subnanomolar. The effects of these LRH-1 agonists were then explored in vivo where they were administered to normal mice and it was shown that both ligands produced significantly reduced levels of non-esterified fatty acids and glucose levels in serum as well as a reduction of hepatic triglycerides. These effects were further explored in two mouse models of insulin resistance, db/db and diet induced obese (DIO) mice and the results were equally striking. DLPC treatment of insulin-resistant leptin-receptor deficient db/db mice for two weeks saw improvements in glucose homeostasis as well as lower fasting serum insulin levels and significantly lowered hepatic triglyceride levels in these animals compared to vehicle control.

Figure 4

Chemical structure of DLPC and DUPC (Dilauroyl phosphatidylcholine and diundecanoyl phosphatidylcholine), two LRH-1 ligands.

To further confirm the role of LRH-1 in this pathway, DIO mice, that either expressed wild-type hepatic LRH-1 or were knocked out for hepatic LRH-1, were fed a high fat diet to induce obesity and insulin resistance. These animals were then continued on the diet with the addition of either DLPC or vehicle control for an additional three weeks and then the same parameters of glucose homeostasis were measured. It was determined that consistent with the db/db mice, the DIO mice containing wild-type hepatic LRH-1 and treated with DLPC showed marked improvement of glucose homeostasis that was absent from the mice containing the LRH-1 knockout. Moreover, these animals displayed increased insulin sensitivity, decreased hepatic triglyceride levels, decreased non-esterified fatty acids and their livers appeared less pale and fatty than the animals with the LRH-1 knockout given DLPC. These data illustrate the utility of these two novel LRH-1 agonists in further elucidating the mechanisms that control this pathway and identifies a potential new target for the intervention into metabolic disease. Furthermore, the results suggest that a targeted synthetic chemistry approach to targeting LRH-1 is warranted.

Summary

Defining both natural and synthetic ligands for orphan NRs continues to be a rich area and discoveries in the areas of RORs and LRH-1 over the past 2 years suggests that this group of NRs as well as additional orphan NRs may develop into validated drug targets. Beyond autoimmunity, the RORs offer the potential for development of drugs targeting a range of disorders. Both RORα and RORγ play important roles in glucose and lipid metabolism, which is exemplified by the phenotypes of mice with mutations in RORα or RORγ {Mamontova, 1998 #772}{Lau, 2008 #776}{Kang, 2007 #748}. During the investigation of the effects of SR1001, we reported that metabolic genes known to be regulated by ROR were also affected {Solt, 2011 #1238}. Furthermore, we also demonstrated that a RORα-selective agonist, SR3335, suppresses hepatic glucose output in vivo{Kumar, 2011 #1240}. Thus, there are clear opportunities for assessing the ability of synthetic RORα/γ ligands for treatment of metabolic disorders such as type 2 diabetes. Currently, much less is known about targeting RORβ with small molecule synthetic ligands. RORβ expression is limited to the CNS and plays a critical role in regulation of the central circadian rhythm, but RORβ null mice also display reduced anxiety {Masana, 2007 #888}. Although RORα also plays a critical role in regulation of the circadian rhythm, the restricted pattern of expression of RORβ suggests that one may be able to develop RORβ-selective compounds that would modulate the central circadian rhythm without affecting the periphery.

The utilization of the TZD class of PPARγ agonists in the clinic has been declining significantly due to the association of these compounds with a range of side effects that has even led to the removal of drugs from the market. The observation that a new class of “modulator” compounds that selectively alter the post-translational modification of this receptor leading to “selective” pharmacology offers potential for a new class of PPARγ ligands that would offer the beneficial insulin sensitization effects without the detrimental side effects that are associated with typical agonists. This approach, while clearly promising, is in early stages and it is unclear if this will yield a superior drug in the clinic. With the array of selective modulators being developed for various nuclear receptors, it is interesting to speculate whether this method of selective modulation of post-transcriptional modification of the receptor leading to selective pharmacology will be applicable to a wider array of receptors.

The observation that DLPC regulates LRH-1 activity in vivo and is therapeutic for type 2 diabetes begs for a classical medicinal chemistry approach to be applied to this orphan receptor. With this recent publication from the Moore lab {Lee, 2011#1776}, it is clear that there will be several groups investigating the potential for development of synthetic ligands that target LRH-1. This class of nuclear receptor ligands may also offer a unique method for treatment of metabolic diseases.

Acute effects of feeding fructose, glucose and sucrose on blood lipid levels and systemic inflammation

Faizan Jameel, Melinda Phang, […], and Manohar L Garg

Abstract

Background

Recent studies have demonstrated a relationship between fructose consumption and risk of developing metabolic syndrome. Mechanisms by which dietary fructose mediates metabolic changes are poorly understood. This study compared the effects of fructose, glucose and sucrose consumption on post-postprandial lipemia and low grade inflammation measured as hs-CRP.

Methods

This was a randomized, single blinded, cross-over trial involving healthy subjects (n = 14). After an overnight fast, participants were given one of 3 different isocaloric drinks, containing 50 g of either fructose or glucose or sucrose dissolved in water. Blood samples were collected at baseline, 30, 60 and 120 minutes post intervention for the analysis of blood lipids, glucose, insulin and high sensitivity C-reactive protein (hs-CRP).

Results

Glucose and sucrose supplementation initially resulted in a significant increase in glucose and insulin levels compared to fructose supplementation and returned to near baseline values within 2 hours. Change in plasma cholesterol, LDL and HDL-cholesterol (measured as area under curve, AUC) was significantly higher when participants consumed fructose compared with glucose or sucrose (P < 0.05). AUC for plasma triglyceride levels however remained unchanged regardless of the dietary intervention. Change in AUC for hs-CRP was also significantly higher in subjects consuming fructose compared with those consuming glucose (P < 0.05), but not sucrose (P = 0.07).

Conclusion

This study demonstrates that fructose as a sole source of energy modulates plasma lipids and hsCRP levels in healthy individuals. The significance of increase in HDL-cholesterol with a concurrent increase in LDL-cholesterol and elevated hs-CRP levels remains to be delineated when considering health effects of feeding fructose-rich diets.

Registration number for clinical trials

ACTRN12614000431628

Introduction

Fructose, commonly known as fruit sugar, is also a major component of sweeteners such as table sugar, honey and high fructose corn syrup (HFCS). Fructose intake has quadrupled since the beginning of 20th century, partly because of the introduction of HFCS [1]. Increased fructose consumption can lead to a parallel rise in cardiovascular disease risk factors, i.e. increase in blood lipids [2, 3], development of insulin resistance [4, 5], alteration in the production of satiety hormones (insulin, leptin and ghrelin) [3], increase in inflammatory biomarkers [6, 7] and increase in obesity [5, 8]. Since similar effects do not occur following the intake of starch or glucose, it has been proposed that fructose-induced metabolic changes are not mediated by excessive sugar intake in general, but are specific to fructose. Precise underlying mechanisms by which fructose consumption may induce negative metabolic effects are not clear. One recent study demonstrated that in young healthy individuals, consumption of glucose and fructose drinks resulted in markedly different hemodynamic responses, with fructose stimulating a sustained increase in blood pressure [9]. These observations support the concept that diets with repeated fructose loads may, over time, contribute to increased cardiovascular disease risk.

The aim of this study was to investigate the effects of fructose compared to glucose and sucrose consumption, on postprandial lipemia and low grade inflammation in healthy subjects. Previous studies have examined the effects of feeding sugars as part of a meal on cardiovascular disease indices. In the current study, we looked at postprandial lipid and low grade inflammation following a single dose of sugary drink given as a sole source of energy after an overnight fast.

Methods

Study population

Healthy male and female adults (n = 14) between the ages of 18-60 years were recruited by advertisement and underwent study procedures at the Nutraceuticals Research Group Clinic rooms, University of Newcastle, NSW, Australia. Exclusion criteria were: diagnosed hyperlipidaemia, diabetes, gastrointestinal disorders, currently on fructose/sugar restricted diet, vegan diet or weight loss program, undergone any surgical procedure for obesity, pregnant or lactating mother, taking lipid-lowering or anti-inflammatory drugs and BMI >30 kg/m². Participants were asked to complete a medical questionnaire, International Physical Activity Questionnaire (IPAQ) [10] and a 24 hr food record. Approval for the study was granted by the Human Research Ethics Committee of the University of Newcastle, Australia. All participants provided written informed consent and the study was conducted in accordance with The Declaration of Helsinki. The trial was registered with the Australian & New Zealand Clinical Trials Registry (ACTRN12614000431628). Body composition was assessed by bioimpedance analysis (BIA) using single frequency bioelectrical impedance apparatus (Maltron International, Essex, UK). Measurements were conducted in the supine position, with participants wearing light clothing and without shoes, in the morning after a minimum 10 hour fast. Participants were asked to refrain from physical exertion and alcohol consumption for 24 hours prior to testing.

Study design

The trial was a randomised, single blinded, controlled cross-over intervention trial. Participants visited the research facility on three separate occasions, where they consumed one of 3 different isocaloric sugary drinks on each occasion, with a minimum of one week wash out period in between. The participants were randomised to consume: 1) 50 g fructose dissolved in 300 ml of water 2) 50 g glucose dissolved in 300 ml of water and 3) 50 g sucrose dissolved in 300 ml of water. Each sugar drink contained 10 ml of lemon juice to provide a more uniform and palatable taste. Participants were asked to consume the sweetened drinks within 2-3 minutes and compliance was observed. Block randomization technique was used for allocation of participants to treatment arms. During each visit, a fasting blood sample was collected prior to supplementation, then 30, 60 and 120 minutes following intake of the sugary drink. The participants remained in the research facility until the final sample was collected and were asked to limit physical activity during their time in the research facility.

Laboratory methods

Blood samples at base line, 30, 60 and 120 minutes were collected into tubes pre-coated with EDTA, lithium heparin and sodium fluoride by venepuncture. EDTA blood tubes were centrifuged for 10 minutes at 3000 g at 4°C for separation of plasma and stored at -80°C for further use. The lithium heparin tubes for blood lipids and sodium fluoride tubes for blood glucose and insulin measurement were analysed by Hunter New England Area Pathology Services (Newcastle). Twenty four hour food recalls were collected by face to face interview by an in-house dietician. Food records collected from participants were entered into FoodWorks Version 7.0.291 database (Xyris Software Pty Ltd, Queensland, Australia) to analyse daily energy and nutrient intake of participants.

Statistical analysis

All data are presented as mean ± SEM. Area under the curve (AUC) was calculated by the trapezoid method. Preliminary assumption testing was done to check for normality, linearity, outliers and homogeneity of variance with no serious violations noted for all test variables within the three different groups of fructose, glucose and sucrose. Comparisons between different groups were made with one-way repeated measures ANOVA and post hoc Tukey testing. A probability level of p < 0.05 was adopted throughout to determine statistical significance unless otherwise mentioned. All statistical analyses were carried out with SPSS software (version 21.0; SPSS Inc., Chicago, IL, USA).

Results

All participants were healthy and their baseline values of anthropometric measurements and blood biomarkers were within normal range (Table 1).

Table 1

Baseline values of anthropometric measurements, blood biomarkers & energy and nutrients intakes of study participants

As shown in Figure 1A, at 30 minutes, fructose consumption was followed by an increase in blood glucose levels that was significantly lower than following glucose and sucrose consumption. At 60 and 120 minutes there were no differences between the 3 groups. The overall change in blood glucose levels followed by fructose consumption measured as area under the curve (AUC), was significantly lower than following glucose supplementation (Figure 1B).

Figure 1

Kinetics of change and area under the curve (AUC) for blood glucose (mmol/L) (A and B respectively) and insulin (mIU/L) (C and D respectively) after the fructose, glucose or sucrose supplementations. Values without a common superscript are significantly …

Figure 1C demonstrates that after 30 minutes, fructose consumption led to a smaller increase in insulin levels than glucose or sucrose. At 60 minutes, insulin levels in the fructose fed group remained lower than the glucose fed group. However, at 120 minutes, there were no differences in insulin levels across intervention groups. The overall increase in the insulin levels, measured as AUC, was significantly lower when participants consumed fructose compared to glucose or sucrose (Figure 1D).

Fructose consumption led to an increase in total cholesterol compared to glucose and sucrose consumption (Figure 2A). The effects were still apparent at 60 minutes, however at 120 minutes there were no differences between groups. The overall increase in plasma total cholesterol measured as AUC was significantly higher when participants consumed fructose compared to glucose or sucrose (Table 2). At 30 minutes after fructose consumption we observed an increase in LDL-cholesterol compared to glucose and sucrose (Figure 2B). The effects were still apparent at 60 minutes. However, at 120 minutes there were no differences between groups. Overall, the increase in LDL cholesterol measured as AUC was significantly higher when participants consumed fructose compared to glucose or sucrose (Table 2). Similarly, fructose consumption was followed by an increase in HDL-cholesterol at 30 minutes in comparison to glucose and sucrose (Figure 2C). The effects were still apparent at 60 minutes; however, at 120 minutes there were no differences between groups. The overall increase in HDL cholesterol measured as AUC was significantly higher when participants consumed fructose compared to glucose or sucrose (Table 2).

Figure 2

Kinetics of change for (A) total cholesterol (mmol/L); (B) LDL-C (mmol/L); (C)HDL-C (mmol/L) and (D) triglyceride (mmol/L) after the fructose, glucose or sucrose supplementations. Values without a common superscript are significantly different; P < 0.05. …

Table 2

Area under curve (AUC) for blood lipids derived from kinetics of change

Comparison of all treatment groups revealed no significant difference in TG levels at 30 minutes. At 60 minutes, subjects fed fructose had lower TG levels compared to glucose. At 120 minutes there were no differences between groups (Figure 2D). There were overall no significant differences in plasma triglyceride levels (measured as AUC) regardless of the dietary intervention (Table 2). Comparison between all treatment groups revealed no significant change in the ratio of total/HDL-cholesterol at all the time points (p > 0.005). Furthermore, the overall change in the ratio of total/HDL-cholesterol measured as AUC was not different between groups (Table 2).

Figure 3A demonstrates that fructose consumption was followed by an increase in hs-CRP level at 30 minutes when compared to glucose and sucrose. At 60 minutes, hs-CRP was not different compared to glucose or sucrose and at 120 minutes there were no differences between groups. There was, however, an overall increase in hs-CRP levels measured as AUC in subjects who consumed fructose compared with those who consumed glucose (p < 0.05), but not sucrose (Figure 3B).

Figure 3

Kinetics of change (A) and area under the curve (AUC) (B) for CRP (mg/L) after the fructose, glucose or sucrose supplementations. Values without a common superscript are significantly different; P < 0.05.

Discussion

This study was designed to examine the metabolic consequences of sugar consumption when it is used as a sole source of energy. Participants consumed fructose in the fasting state in the morning; therefore, majority of the sugar consumed would be used to produce energy and/or partly used to replenish glycogen stores at this time of day [11]. Fructose was a sole source of energy without accompanying meal and there was no other nutrient to augment postprandial lipemia. Consumption of sugar sweetened beverages in the morning in the fasting state separated the effect of fructose from excess energy intake which may be a confounder in the overfeeding studies [11]. This is the first study to report the consequences of consuming a beverage containing fructose, glucose or sucrose as a sole source of energy, on postprandial lipid levels and inflammation markers. Acute fructose consumption in a single dose of 50 g/day which provided approximately 8% of daily energy in the form of a beverage, resulted in a significant increase in the plasma levels of total, LDL and HDL cholesterol and the acute phase pro-inflammatory marker hs-CRP, compared to the same dose of glucose or sucrose. Interestingly, no significant change in TG levels was observed.

The change in fasting glucose and insulin responses was modest in fructose compared with glucose and sucrose groups. This modest increase in the glucose and insulin levels after fructose consumption is consistent with previous studies [12–14]. The blunted rise in insulin in response to fructose consumption is consistent with the blunted rise in blood glucose level, but may also be partly attributed to less release of intestinal incretin hormone that binds to β-cells of the pancreas leading to reduce secretion of insulin [15].

Changes in total, LDL and HDL-cholesterol levels were significantly higher when participants consumed fructose compared with glucose or sucrose sweetened beverage. Previous studies examining postprandial lipemia following fructose consumption were either focused on triglyceride levels only [11, 14, 16–19] or demonstrate heterogeneous results. Two studies showed no effects of fructose on plasma total, LDL or HDL-cholesterol levels [20, 21], while another 2 studies [2, 22] showed a significant increase in fasting serum total and LDL cholesterol following 4-5 weeks of consuming fructose-rich diets compared to the starch diet. The reason for the increase in postprandial levels of total, LDL and HDL cholesterol in subjects who consumed fructose in our study is not known. Since no nutrients, other than sugars, were included in the test beverages, the lipoproteins measured were almost exclusively of hepatic origin. Whether fructose can influence total and LDL-cholesterol levels by blocking LDL-receptors or affect HDL cholesterol via CETP or reverse cholesterol transport is not known, therefore, merits further investigation.

Dietary fructose has been previously shown to cause either no change [2, 21, 23, 24] or an increase in fasting plasma triglycerides in healthy subjects [20, 25]. Our results showed no significant change in postprandial triglyceride levels irrespective of the type of sugar. These findings are in agreement with a meta-analysis reporting no significant change in post-prandial TG level unless the amount of fructose exceeds 50 g/day [26]. On the other hand, the present results are in contrast with literature reporting an increase in TG after acute fructose consumption [3, 11, 14, 16–18, 25, 27]. This disagreement may be due to the accompanying meal with consumption of the fructose beverage in previously published studies. In our study, due to the absence of other energy yielding nutrients, the clearance rate of triglycerides can be expected to be higher, resulting in overall no change. Moreover the shorter duration (2 hours) of our study compared to the study by Bohannan et al. [19] (5 hours) may account for the discrepancy in the two studies. Therefore, the lipemic effects of fructose may depend on the dose and duration of fructose feeding and whether fructose is consumed in the presence or absence of other energy nutrients.

The pro-inflammatory biomarker that we examined in this study was hs-CRP. The area under the curve for hs-CRP level was significantly increased in the fructose group compared with glucose, but not with sucrose. This is the first time, to our knowledge, in healthy and normal weight adult subjects, that acute fructose consumption has been shown to increase hs-CRP levels. Previous studies reporting an increase in hs-CRP level were either conducted in a mixed population of lean and overweight individuals [12] or a long term intervention study [6]. The proposed mechanism of fructose-induced oxidative stress and inflammation markers (TNFα, IL-6, IL-1β) [28] potentially resulting in an increase synthesis of hs-CRP merits further investigation. Fructose has been shown to induce oxidative stress in cellular [29] and animal models [30], thereby, may result in elevated levels of pro-inflammatory mediators. Whether fructose can directly (without conversion to fat) influence inflammation pathways (leukotriene synthesis, expression of adhesion molecules etc) remains to be delineated. In conclusion, this study demonstrates that fructose as a sole source of energy modulates plasma lipids and hsCRP levels in healthy individuals. However, the significance of increase in HDL-cholesterol with a concurrent increase in LDL-cholesterol and elevated hsCRP levels remains to be delineated when considering health effects of feeding fructose-rich diets.

Acknowledgements

This study was funded by a grant from the Hunter Medical Research Institute. The authors declare no conflict of interest.

Secret of Eternal Youth; Teaching from the Centenarian Hot Spots (“Blue Zones”)

Badri N Mishra

The euphoria of modern day health achievements is in an epidemiological cross road. We are going to lose out the hard caught health benefits to modern monsters such as obesity and its associated diseases. For example, the present American life expectancy of 77.8 years is expected to plummet due to the current trend of noncommunicable diseases.(1) However, there are zones (blue zones) on our planet where people live like in fairy tales, holding the secret of eternal youth.(2) Time has come to explore these areas to enrich our academic and research.

Scientific exploration has shown some basic factors as being behind a long lifespan: a plant-based diet; regular, low-intensity activity; an investment in family; a sense of faith; and purpose.(3–8)

Blue Zones

Okinawa Island in Japan is famous for the longest disability-free life expectancy in the world.(4–10) Other “blue zones” are Sardinia (Italy) with the highest concentration of centenarians and the community of Seventh Day Adventists of Loma Linda in California. Nicoya Peninsula in Costa Rica is another “blue zone” where healthy centenarians live in a solid support network of friends and family.(6)

People who make it to a hundred tend to be nice. They drink from the fountain of life by being likable and drawing people to them. As an example, Nicoya Peninsula has the lowest middle-age mortality in the world. Here a 60-year-old has more than fourfold better chance of making it to 90 than a 60-year-old in America.(7) They spend 20% the amount on public health in contrast to American, but they spend it in the right places.(6)

So set up your life, your home environment, your social environment, and your workplace so that you are constantly nudged into behaviors that favor longevity. Let us look at the blue zone in Okinawa, these people are consistently eating off of small plates. One of the cues for fullness is an empty plate, so stock your cupboard with smaller plates. Add decades to your life by reconnecting with your religion and investing in your family.(6–10)

The Okinawa Case

Okinawa, the main island of Ryukyu in Japan, is packed with natural adversities. It witnessed a fierce and crucial battle during World War II. Today, the US military bases occupy 20% of its surface and the Okinawa Prefecture is the poorest province of Japan.(9)

In contradiction to the above facts, the heaven of longevity is here. Besides holding the record for longevity and centenaries of the world, it is the only place where 80-90 year-olds live like persons 30 years younger. Ancient Chinese legends already called Okinawa “the land of the immortals”. Here you see 100-year-old persons that are not even thinking about retirement. The prevalence of centenarians is of 35 for each 100 000 inhabitants.(8–11)

The Okinawa inhabitants reach ages similar to the Japanese average of 86 for women and 78 for men.(9) However, the real encouraging factor is not that people reach these ages, but they grow old in a much better state. The statistics reveal a significantly lower risk of heart attack and stroke, cancer, osteoporosis, Alzheimer. Some in their 90’s can honestly vouch that they still have an active sex life.(11)

Research show that there are two main factors behind the longevity on this island: alimentation and a healthy lifestyle that experts believe can be imitated.

Okinawa Diet

Vegetables grown on this volcanic soil are rich in vitamin C and polyphenol, which have antioxidant functions. They are a great source of dietary fiber and potassium. People eat 300 g of vegetables a day. The increased consumption of yellow-green Okinawa vegetables that include soybeans, tofu and goya – a bitter gourd improves biological health indices. Older Okinawans eat probably three or four times more of vegetables than that of the younger generations.(9)

Okinawan women also have a very high intake of natural estrogens through their diet, mainly from the soy they consume. Soy contains phytoestrogens, or plant estrogens called flavonoids. The other important major phytoestrogens are lignans, which are derived from flax and other grains. All plants, especially legumes, onions, and broccoli, contain these natural estrogens, but not nearly in the same quantity as soy and flax. Recent double-blind placebo controlled studies support the ability of soy isoflavones to slow the bone loss that occurs with menopause.(11)

Elderly were found to have impressively young, clean arteries, low cholesterol, and low homocysteine levels when compared to Westerners. They have low blood levels of free radicals. The elders had significantly lower levels of lipid peroxide-compelling evidence that they suffer less free-radical-induced damage.(11) These factors help reduce their risk for coronary heart disease by up to 80% and keep stroke levels low.

Okinawan centenarians have been lean throughout with an average body mass index (BMI) of 18 to 22. They traditionally keep eating a low-calorie, low glycemic load diet, practice calorie control in a cultural habit known as hara hachi bu (only eating until they are 80% full), and staying physically active the natural way.(11)

Okinawa Social Support

Nowhere is a strong sense of purpose more acute than in Japan, where the concept has its own name: “ikigai’ (You see it over and over again).(4) The elders here have low depression levels. You can see persons aged 90-100 on motorcycles or mountain bikes on the streets. Most of them practice karate, kendo, dancing, walk daily several kilometers, and even work on vegetable gardens and after that sell the products.

These people do not go to fitness gyms or do jogging; they can, however, practice profound respiration, tai-chi (a type of yoga), and gardening and other activities in the open that positively influence the stress level.

They are preoccupied by hobbies, linked to a social network that makes them feel connected to the environment and their fellows, and helps develop their spiritual side. Physical activity is not isolated, but has an objective, making the elders feel active members of the community.

Another factor in Okinawa is that people take care of each other, forming more coherent and supportive links than in the western world. They have a positive attitude toward life which explains the extremely low levels of stress experienced by these elders. Of course, there is a genetic factor that may also be contributing to this vitality.

Longevity Gene

The key to a long life is now believed to be a mix of genetics and environmental factors such as health habits and stress free events.(10)

While talking about gene, it is worth mentioning the effort of the New England Centenarian Study at Boston University. It has gathered DNA information from about 100 super centenarians (people who live to 110 and beyond). Study suggests that several alleles of the HLA-DRB1 and/or HLA-DQ genes are involved in human longevity.(10) The analysis of HLA class II genes of Okinawan centenarians using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method yielded that the frequencies of DQB1*0503, DQA1*0101 (04) and DQA1*05 were increased in the centenarians, whereas those of DQA1*0102, DQA1*0103 and DQB1*0604 were decreased. Similarly, for the DRB1 gene, the frequencies of DRB1*0101, DRB1*1201 and DRB1*1401 were increased in the centenarians, whereas those of DRB1*0403 and DRB1*1302 were decreased.

Conclusion

Although the blue zones are found in four very geographically and culturally different parts of the world, there are nine characteristics common to all of them that are portable to any location and can be used to make healthy lifestyle changes. They include making low-intensity physical activity part of one’s daily routine, building good relationships with friends and family, eating a diet lighter on meat and excess calories and heavier on plants, and finding a purpose for and sense of meaning in your life.

You can optimize your lifestyle, you may gain back an extra decade of good life you’d otherwise miss. Adopting any one of these nine will immediately improve your life expectancy at any age.

The sugar conspiracy | Sugar | The Guardian

Ian Leslie

ILsugar 02 jor 0407 031 Photograph: Peter Gamlen

In 1972, a British scientist sounded the alarm that sugar – and not fat – was the greatest danger to our health. But his findings were ridiculed and his reputation ruined. How did the world’s top nutrition scientists get it so wrong for so long?

Thu 7 Apr 2016 01.00 EDT

Last modified on Thu 2 Aug 2018 14.35 EDT

 

Robert Lustig is a paediatric endocrinologist at the University of California who specialises in the treatment of childhood obesity. A 90-minute talk he gave in 2009, titled Sugar: The Bitter Truth, has now been viewed more than six million times on YouTube. In it, Lustig argues forcefully that fructose, a form of sugar ubiquitous in modern diets, is a “poison” culpable for America’s obesity epidemic.

A year or so before the video was posted, Lustig gave a similar talk to a conference of biochemists in Adelaide, Australia. Afterwards, a scientist in the audience approached him. Surely, the man said, you’ve read Yudkin. Lustig shook his head. John Yudkin, said the scientist, was a British professor of nutrition who had sounded the alarm on sugar back in 1972, in a book called Pure, White, and Deadly.

“If only a small fraction of what we know about the effects of sugar were to be revealed in relation to any other material used as a food additive,” wrote Yudkin, “that material would promptly be banned.” The book did well, but Yudkin paid a high price for it. Prominent nutritionists combined with the food industry to destroy his reputation, and his career never recovered. He died, in 1995, a disappointed, largely forgotten man.

Perhaps the Australian scientist intended a friendly warning. Lustig was certainly putting his academic reputation at risk when he embarked on a high-profile campaign against sugar. But, unlike Yudkin, Lustig is backed by a prevailing wind. We read almost every week of new research into the deleterious effects of sugar on our bodies. In the US, the latest edition of the government’s official dietary guidelines includes a cap on sugar consumption. In the UK, the chancellor George Osborne has announced a new tax on sugary drinks. Sugar has become dietary enemy number one.

This represents a dramatic shift in priority. For at least the last three decades, the dietary arch-villain has been saturated fat. When Yudkin was conducting his research into the effects of sugar, in the 1960s, a new nutritional orthodoxy was in the process of asserting itself. Its central tenet was that a healthy diet is a low-fat diet. Yudkin led a diminishing band of dissenters who believed that sugar, not fat, was the more likely cause of maladies such as obesity, heart disease and diabetes. But by the time he wrote his book, the commanding heights of the field had been seized by proponents of the fat hypothesis. Yudkin found himself fighting a rearguard action, and he was defeated.

Not just defeated, in fact, but buried. When Lustig returned to California, he searched for Pure, White and Deadly in bookstores and online, to no avail. Eventually, he tracked down a copy after submitting a request to his university library. On reading Yudkin’s introduction, he felt a shock of recognition.

“Holy crap,” Lustig thought. “This guy got there 35 years before me.”

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In 1980, after long consultation with some of America’s most senior nutrition scientists, the US government issued its first Dietary Guidelines. The guidelines shaped the diets of hundreds of millions of people. Doctors base their advice on them, food companies develop products to comply with them. Their influence extends beyond the US. In 1983, the UK government issued advice that closely followed the American example.

The most prominent recommendation of both governments was to cut back on saturated fats and cholesterol (this was the first time that the public had been advised to eat less of something, rather than enough of everything). Consumers dutifully obeyed. We replaced steak and sausages with pasta and rice, butter with margarine and vegetable oils, eggs with muesli, and milk with low-fat milk or orange juice. But instead of becoming healthier, we grew fatter and sicker.

Look at a graph of postwar obesity rates and it becomes clear that something changed after 1980. In the US, the line rises very gradually until, in the early 1980s, it takes off like an aeroplane. Just 12% of Americans were obese in 1950, 15% in 1980, 35% by 2000. In the UK, the line is flat for decades until the mid-1980s, at which point it also turns towards the sky. Only 6% of Britons were obese in 1980. In the next 20 years that figure more than trebled. Today, two thirds of Britons are either obese or overweight, making this the fattest country in the EU. Type 2 diabetes, closely related to obesity, has risen in tandem in both countries.

At best, we can conclude that the official guidelines did not achieve their objective; at worst, they led to a decades-long health catastrophe. Naturally, then, a search for culprits has ensued. Scientists are conventionally apolitical figures, but these days, nutrition researchers write editorials and books that resemble liberal activist tracts, fizzing with righteous denunciations of “big sugar” and fast food. Nobody could have predicted, it is said, how the food manufacturers would respond to the injunction against fat – selling us low-fat yoghurts bulked up with sugar, and cakes infused with liver-corroding transfats.

Nutrition scientists are angry with the press for distorting their findings, politicians for failing to heed them, and the rest of us for overeating and under-exercising. In short, everyone – business, media, politicians, consumers – is to blame. Everyone, that is, except scientists.

But it was not impossible to foresee that the vilification of fat might be an error. Energy from food comes to us in three forms: fat, carbohydrate, and protein. Since the proportion of energy we get from protein tends to stay stable, whatever our diet, a low-fat diet effectively means a high-carbohydrate diet. The most versatile and palatable carbohydrate is sugar, which John Yudkin had already circled in red. In 1974, the UK medical journal, the Lancet, sounded a warning about the possible consequences of recommending reductions in dietary fat: “The cure should not be worse than the disease.”

Still, it would be reasonable to assume that Yudkin lost this argument simply because, by 1980, more evidence had accumulated against fat than against sugar.

After all, that’s how science works, isn’t it?

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If, as seems increasingly likely, the nutritional advice on which we have relied for 40 years was profoundly flawed, this is not a mistake that can be laid at the door of corporate ogres. Nor can it be passed off as innocuous scientific error. What happened to John Yudkin belies that interpretation. It suggests instead that this is something the scientists did to themselves – and, consequently, to us.

We tend to think of heretics as contrarians, individuals with a compulsion to flout conventional wisdom. But sometimes a heretic is simply a mainstream thinker who stays facing the same way while everyone around him turns 180 degrees. When, in 1957, John Yudkin first floated his hypothesis that sugar was a hazard to public health, it was taken seriously, as was its proponent. By the time Yudkin retired, 14 years later, both theory and author had been marginalised and derided. Only now is Yudkin’s work being returned, posthumously, to the scientific mainstream.

These sharp fluctuations in Yudkin’s stock have had little to do with the scientific method, and a lot to do with the unscientific way in which the field of nutrition has conducted itself over the years. This story, which has begun to emerge in the past decade, has been brought to public attention largely by sceptical outsiders rather than eminent nutritionists. In her painstakingly researched book, The Big Fat Surprise, the journalist Nina Teicholz traces the history of the proposition that saturated fats cause heart disease, and reveals the remarkable extent to which its progress from controversial theory to accepted truth was driven, not by new evidence, but by the influence of a few powerful personalities, one in particular.

Teicholz’s book also describes how an establishment of senior nutrition scientists, at once insecure about its medical authority and vigilant for threats to it, consistently exaggerated the case for low-fat diets, while turning its guns on those who offered evidence or argument to the contrary. John Yudkin was only its first and most eminent victim.

Today, as nutritionists struggle to comprehend a health disaster they did not predict and may have precipitated, the field is undergoing a painful period of re-evaluation. It is edging away from prohibitions on cholesterol and fat, and hardening its warnings on sugar, without going so far as to perform a reverse turn. But its senior members still retain a collective instinct to malign those who challenge its tattered conventional wisdom too loudly, as Teicholz is now discovering.

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To understand how we arrived at this point, we need to go back almost to the beginning of modern nutrition science. On 23 September, 1955, US President Dwight Eisenhower suffered a heart attack. Rather than pretend it hadn’t happened, Eisenhower insisted on making details of his illness public. The next day, his chief physician, Dr Paul Dudley White, gave a press conference at which he instructed Americans on how to avoid heart disease: stop smoking, and cut down on fat and cholesterol. In a follow-up article, White cited the research of a nutritionist at the University of Minnesota, Ancel Keys.

Heart disease, which had been a relative rarity in the 1920s, was now felling middle-aged men at a frightening rate, and Americans were casting around for cause and cure. Ancel Keys provided an answer: the “diet-heart hypothesis” (for simplicity’s sake, I am calling it the “fat hypothesis”). This is the idea, now familiar, that an excess of saturated fats in the diet, from red meat, cheese, butter, and eggs, raises cholesterol, which congeals on the inside of coronary arteries, causing them to harden and narrow, until the flow of blood is staunched and the heart seizes up.

Ancel Keys was brilliant, charismatic, and combative. A friendly colleague at the University of Minnesota described him as, “direct to the point of bluntness, critical to the point of skewering”; others were less charitable. He exuded conviction at a time when confidence was most welcome. The president, the physician and the scientist formed a reassuring chain of male authority, and the notion that fatty foods were unhealthy started to take hold with doctors, and the public. (Eisenhower himself cut saturated fats and cholesterol from his diet altogether, right up until his death, in 1969, from heart disease.)

Many scientists, especially British ones, remained sceptical. The most prominent doubter was John Yudkin, then the UK’s leading nutritionist. When Yudkin looked at the data on heart disease, he was struck by its correlation with the consumption of sugar, not fat. He carried out a series of laboratory experiments on animals and humans, and observed, as others had before him, that sugar is processed in the liver, where it turns to fat, before entering the bloodstream.

He noted, too, that while humans have always been carnivorous, carbohydrates only became a major component of their diet 10,000 years ago, with the advent of mass agriculture. Sugar – a pure carbohydrate, with all fibre and nutrition stripped out – has been part of western diets for just 300 years; in evolutionary terms, it is as if we have, just this second, taken our first dose of it. Saturated fats, by contrast, are so intimately bound up with our evolution that they are abundantly present in breast milk. To Yudkin’s thinking, it seemed more likely to be the recent innovation, rather than the prehistoric staple, making us sick.

John Yudkin was born in 1910, in the East End of London. His parents were Russian Jews who settled in England after fleeing the pogroms of 1905. Yudkin’s father died when he was six, and his mother brought up her five sons in poverty. By way of a scholarship to a local grammar school in Hackney, Yudkin made it to Cambridge. He studied biochemistry and physiology, before taking up medicine. After serving in the Royal Army Medical Corps during the second world war, Yudkin was made a professor at Queen Elizabeth College in London, where he built a department of nutrition science with an international reputation.

Ancel Keys was intensely aware that Yudkin’s sugar hypothesis posed an alternative to his own. If Yudkin published a paper, Keys would excoriate it, and him. He called Yudkin’s theory “a mountain of nonsense”, and accused him of issuing “propaganda” for the meat and dairy industries. “Yudkin and his commercial backers are not deterred by the facts,” he said. “They continue to sing the same discredited tune.” Yudkin never responded in kind. He was a mild-mannered man, unskilled in the art of political combat.

That made him vulnerable to attack, and not just from Keys. The British Sugar Bureau dismissed Yudkin’s claims about sugar as “emotional assertions”; the World Sugar Research Organisation called his book “science fiction”. In his prose, Yudkin is fastidiously precise and undemonstrative, as he was in person. Only occasionally does he hint at how it must have felt to have his life’s work besmirched, as when he asks the reader, “Can you wonder that one sometimes becomes quite despondent about whether it is worthwhile trying to do scientific research in matters of health?”

Throughout the 1960s, Keys accumulated institutional power. He secured places for himself and his allies on the boards of the most influential bodies in American healthcare, including the American Heart Association and the National Institutes of Health. From these strongholds, they directed funds to like-minded researchers, and issued authoritative advice to the nation. “People should know the facts,” Keys told Time magazine. “Then if they want to eat themselves to death, let them.”

This apparent certainty was unwarranted: even some supporters of the fat hypothesis admitted that the evidence for it was still inconclusive. But Keys held a trump card. From 1958 to 1964, he and his fellow researchers gathered data on the diets, lifestyles and health of 12,770 middle-aged men, in Italy, Greece, Yugoslavia, Finland, Netherlands, Japan and the United States. The Seven Countries Study was finally published as a 211-page monograph in 1970. It showed a correlation between intake of saturated fats and deaths from heart disease, just as Keys had predicted. The scientific debate swung decisively behind the fat hypothesis.

Keys was the original big data guy (a contemporary remarked: “Every time you question this man Keys, he says, ‘I’ve got 5,000 cases. How many do you have?’). Despite its monumental stature, however, the Seven Countries Study, which was the basis for a cascade of subsequent papers by its original authors, was a rickety construction. There was no objective basis for the countries chosen by Keys, and it is hard to avoid the conclusion that he picked only those he suspected would support his hypothesis. After all, it is quite something to choose seven nations in Europe and leave out France and what was then West Germany, but then, Keys already knew that the French and Germans had relatively low rates of heart disease, despite living on a diet rich in saturated fats.

The study’s biggest limitation was inherent to its method. Epidemiological research involves the collection of data on people’s behaviour and health, and a search for patterns. Originally developed to study infection, Keys and his successors adapted it to the study of chronic diseases, which, unlike most infections, take decades to develop, and are entangled with hundreds of dietary and lifestyle factors, effectively impossible to separate.

To reliably identify causes, as opposed to correlations, a higher standard of evidence is required: the controlled trial. In its simplest form: recruit a group of subjects, and assign half of them a diet for, say, 15 years. At the end of the trial, assess the health of those in the intervention group, versus the control group. This method is also problematic: it is virtually impossible to closely supervise the diets of large groups of people. But a properly conducted trial is the only way to conclude with any confidence that X is responsible for Y.

Although Keys had shown a correlation between heart disease and saturated fat, he had not excluded the possibility that heart disease was being caused by something else. Years later, the Seven Countries study’s lead Italian researcher, Alessandro Menotti, went back to the data, and found that the food that correlated most closely with deaths from heart disease was not saturated fat, but sugar.

By then it was too late. The Seven Countries study had become canonical, and the fat hypothesis was enshrined in official advice. The congressional committee responsible for the original Dietary Guidelines was chaired by Senator George McGovern. It took most of its evidence from America’s nutritional elite: men from a handful of prestigious universities, most of whom knew or worked with each other, all of whom agreed that fat was the problem – an assumption that McGovern and his fellow senators never seriously questioned. Only occasionally were they asked to reconsider. In 1973, John Yudkin was called from London to testify before the committee, and presented his alternative theory of heart disease.

A bemused McGovern asked Yudkin if he was really suggesting that a high fat intake was not a problem, and that cholesterol presented no danger.

“I believe both those things,” replied Yudkin.

“That is exactly the opposite of what my doctor told me,” said McGovern.

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In a 2015 paper titled Does Science Advance One Funeral at a Time?, a team of scholars at the National Bureau of Economic Research sought an empirical basis for a remark made by the physicist Max Planck: “A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it.”

The researchers identified more than 12,000 “elite” scientists from different fields. The criteria for elite status included funding, number of publications, and whether they were members of the National Academies of Science or the Institute of Medicine. Searching obituaries, the team found 452 who had died before retirement. They then looked to see what happened to the fields from which these celebrated scientists had unexpectedly departed, by analysing publishing patterns.

What they found confirmed the truth of Planck’s maxim. Junior researchers who had worked closely with the elite scientists, authoring papers with them, published less. At the same time, there was a marked increase in papers by newcomers to the field, who were less likely to cite the work of the deceased eminence. The articles by these newcomers were substantive and influential, attracting a high number of citations. They moved the whole field along.

A scientist is part of what the Polish philosopher of science Ludwik Fleck called a “thought collective”: a group of people exchanging ideas in a mutually comprehensible idiom. The group, suggested Fleck, inevitably develops a mind of its own, as the individuals in it converge on a way of communicating, thinking and feeling.

This makes scientific inquiry prone to the eternal rules of human social life: deference to the charismatic, herding towards majority opinion, punishment for deviance, and intense discomfort with admitting to error. Of course, such tendencies are precisely what the scientific method was invented to correct for, and over the long run, it does a good job of it. In the long run, however, we’re all dead, quite possibly sooner than we would be if we hadn’t been following a diet based on poor advice.

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In a series of densely argued articles and books, including Why We Get Fat(2010), the science writer Gary Taubes has assembled a critique of contemporary nutrition science, powerful enough to compel the field to listen. One of his contributions has been to uncover a body of research conducted by German and Austrian scientists before the second world war, which had been overlooked by the Americans who reinvented the field in the 1950s. The Europeans were practising physicians and experts in the metabolic system. The Americans were more likely to be epidemiologists, labouring in relative ignorance of biochemistry and endocrinology (the study of hormones). This led to some of the foundational mistakes of modern nutrition.

The rise and slow fall of cholesterol’s infamy is a case in point. After it was discovered inside the arteries of men who had suffered heart attacks, public health officials, advised by scientists, put eggs, whose yolks are rich in cholesterol, on the danger list. But it is a biological error to confuse what a person puts in their mouth with what it becomes after it is swallowed. The human body, far from being a passive vessel for whatever we choose to fill it with, is a busy chemical plant, transforming and redistributing the energy it receives. Its governing principle is homeostasis, or the maintenance of energy equilibrium (when exercise heats us up, sweat cools us down). Cholesterol, present in all of our cells, is created by the liver. Biochemists had long known that the more cholesterol you eat, the less your liver produces.

Unsurprisingly, then, repeated attempts to prove a correlation between dietary cholesterol and blood cholesterol failed. For the vast majority of people, eating two or three, or 25 eggs a day, does not significantly raise cholesterol levels. One of the most nutrient-dense, versatile and delicious foods we have was needlessly stigmatised. The health authorities have spent the last few years slowly backing away from this mistake, presumably in the hope that if no sudden movements are made, nobody will notice. In a sense, they have succeeded: a survey carried out in 2014 by Credit Suisse found that 54% of US doctors believe that dietary cholesterol raises blood cholesterol.

To his credit, Ancel Keys realised early on that dietary cholesterol was not a problem. But in order to sustain his assertion that cholesterol causes heart attacks, he needed to identify an agent that raises its levels in the blood – he landed on saturated fats. In the 30 years after Eisenhower’s heart attack, trial after trial failed to conclusively bear out the association he claimed to have identified in the Seven Countries study.

The nutritional establishment wasn’t greatly discomfited by the absence of definitive proof, but by 1993 it found that it couldn’t evade another criticism: while a low-fat diet had been recommended to women, it had never been tested on them (a fact that is astonishing only if you are not a nutrition scientist). The National Heart, Lung and Blood Institute decided to go all in, commissioning the largest controlled trial of diets ever undertaken. As well as addressing the other half of the population, the Women’s Health Initiative was expected to obliterate any lingering doubts about the ill-effects of fat.

It did nothing of the sort. At the end of the trial, it was found that women on the low-fat diet were no less likely than the control group to contract cancer or heart disease. This caused much consternation. The study’s principal researcher, unwilling to accept the implications of his own findings, remarked: “We are scratching our heads over some of these results.” A consensus quickly formed that the study – meticulously planned, lavishly funded, overseen by impressively credentialed researchers – must have been so flawed as to be meaningless. The field moved on, or rather did not.

In 2008, researchers from Oxford University undertook a Europe-wide study of the causes of heart disease. Its data shows an inverse correlation between saturated fat and heart disease, across the continent. France, the country with the highest intake of saturated fat, has the lowest rate of heart disease; Ukraine, the country with the lowest intake of saturated fat, has the highest. When the British obesity researcher Zoë Harcombe performed an analysis of the data on cholesterol levels for 192 countries around the world, she found that lower cholesterol correlated with higher rates of death from heart disease.

In the last 10 years, a theory that had somehow held up unsupported for nearly half a century has been rejected by several comprehensive evidence reviews, even as it staggers on, zombie-like, in our dietary guidelines and medical advice.

The UN’s Food and Agriculture Organisation, in a 2008 analysis of all studies of the low-fat diet, found “no probable or convincing evidence” that a high level of dietary fat causes heart disease or cancer. Another landmark review, published in 2010, in the American Society for Nutrition, and authored by, among others, Ronald Krauss, a highly respected researcher and physician at the University of California, stated “there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD or CVD [coronary heart disease and cardiovascular disease]”.

Many nutritionists refused to accept these conclusions. The journal that published Krauss’s review, wary of outrage among its readers, prefaced it with a rebuttal by a former right-hand man of Ancel Keys, which implied that since Krauss’s findings contradicted every national and international dietary recommendation, they must be flawed. The circular logic is symptomatic of a field with an unusually high propensity for ignoring evidence that does not fit its conventional wisdom.

Gary Taubes is a physicist by background. “In physics,” he told me, “You look for the anomalous result. Then you have something to explain. In nutrition, the game is to confirm what you and your predecessors have always believed.” As one nutritionist explained to Nina Teicholz, with delicate understatement: “Scientists believe that saturated fat is bad for you, and there is a good deal of reluctance toward accepting evidence to the contrary.”

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When obesity started to become recognised as a problem in western societies, it too was blamed on saturated fats. It was not difficult to persuade the public that if we eat fat, we will be fat (this is a trick of the language: we call an overweight person “fat”; we don’t describe a person with a muscular body as “proteiny”). The scientific rationale was also pleasingly simple: a gramme of fat has twice as many calories as a gramme of protein or carbohydrate, and we can all grasp the idea that if a person takes in more calories than she expends in physical activity, the surplus ends up as fat.

Simple does not mean right, of course. It’s difficult to square this theory with the dramatic rise in obesity since 1980, or with much other evidence. In America, average calorific intake increased by just a sixth over that period. In the UK, it actually fell. There has been no commensurate decline in physical activity, in either country – in the UK, exercise levels have increased over the last 20 years. Obesity is a problem in some of the poorest parts of the world, even among communities in which food is scarce. Controlled trials have repeatedly failed to show that people lose weight on low-fat or low-calorie diets, over the long-term.

Those prewar European researchers would have regarded the idea that obesity results from “excess calories” as laughably simplistic. Biochemists and endocrinologists are more likely to think of obesity as a hormonal disorder, triggered by the kinds of foods we started eating a lot more of when we cut back on fat: easily digestible starches and sugars. In his new book, Always Hungry, David Ludwig, an endocrinologist and professor of pediatrics at Harvard Medical School, calls this the “Insulin-Carbohydrate” model of obesity. According to this model, an excess of refined carbohydrates interferes with the self-balancing equilibrium of the metabolic system.

Far from being an inert dumping ground for excess calories, fat tissue operates as a reserve energy supply for the body. Its calories are called upon when glucose is running low – that is, between meals, or during fasts and famines. Fat takes instruction from insulin, the hormone responsible for regulating blood sugar. Refined carbohydrates break down at speed into glucose in the blood, prompting the pancreas to produce insulin. When insulin levels rise, fat tissue gets a signal to suck energy out of the blood, and to stop releasing it. So when insulin stays high for unnaturally long, a person gains weight, gets hungrier, and feels fatigued. Then we blame them for it. But, as Gary Taubes puts it, obese people are not fat because they are overeating and sedentary – they are overeating and sedentary because they are fat, or getting fatter.

Ludwig makes clear, as Taubes does, that this is not a new theory – John Yudkin would have recognised it – but an old one that has been galvanised by new evidence. What he does not mention is the role that supporters of the fat hypothesis have played, historically, in demolishing the credibility of those who proposed it.

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In 1972, the same year Yudkin published Pure, White and Deadly, a Cornell-trained cardiologist called Robert Atkins published Dr Atkins’ Diet Revolution. Their arguments shared a premise – that carbohydrates are more dangerous to our health than fat – though they differed in particulars. Yudkin focused on the evils of one carbohydrate in particular, and didn’t explicitly recommend a high-fat diet. Atkins argued that a high-fat, low-carbohydrate diet was the only viable route to weight loss.

Perhaps the most important difference between the two books was tone. Yudkin’s was cool, polite and reasonable, which reflected his temperament, and the fact that he saw himself as a scientist first and a clinician second. Atkins, resolutely a practitioner rather than an academic, was unbound by gentlemanly conventions. He declared himself furious that he had been “duped” by medical scientists. Unsurprisingly, this attack enraged the nutritional establishment, which hit back hard. Atkins was labelled a fraud, and his diet a “fad”. It was a successful campaign: even today, Atkins’s name brings with it the odour of quackery.

A “fad” implies something new-fangled. But low-carbohydrate, high-fat diets had been popular for well over a century before Atkins, and were, until the 1960s, a method of weight loss endorsed by mainstream science. By the start of the 1970s, that had changed. Researchers interested in the effects of sugar and complex carbohydrates on obesity only had to look at what had happened to the most senior nutritionist in the UK to see that pursuing such a line of inquiry was a terrible career move.

John Yudkin’s scientific reputation had been all but sunk. He found himself uninvited from international conferences on nutrition. Research journals refused his papers. He was talked about by fellow scientists as an eccentric, a lone obsessive. Eventually, he became a scare story. Sheldon Reiser, one of the few researchers to continue working on the effects of refined carbohydrates and sugar through the 1970s, told Gary Taubes in 2011: “Yudkin was so discredited. He was ridiculed in a way. And anybody else who said something bad about sucrose [sugar], they’d say, ‘He’s just like Yudkin.’”

If Yudkin was ridiculed, Atkins was a hate figure. Only in the last few years has it become acceptable to study the effects of Atkins-type diets. In 2014, in a trialfunded by the US National Institutes of Health, 150 men and women were assigned a diet for one year which limited either the amount of fat or carbs they could eat, but not the calories. By the end of the year, the people on the low carbohydrate, high fat diet had lost about 8lb more on average than the low-fat group. They were also more likely to lose weight from fat tissue; the low-fat group lost some weight too, but it came from the muscles. The NIH study is the latest of more than 50 similar studies, which together suggest that low-carbohydrate diets are better than low-fat diets for achieving weight loss and controlling type 2 diabetes. As a body of evidence, it is far from conclusive, but it is as consistent as any in the literature.

The 2015 edition of the US Dietary Guidelines (they are revised every five years) makes no reference to any of this new research, because the scientists who advised the committee – the most eminent and well-connected nutritionists in the country – neglected to include a discussion of it in their report. It is a gaping omission, inexplicable in scientific terms, but entirely explicable in terms of the politics of nutrition science. If you are seeking to protect your authority, why draw attention to evidence that seems to contradict the assertions on which that authority is founded? Allow a thread like that to be pulled, and a great unravelling might begin.

It may already have done. Last December, the scientists responsible for the report received a humiliating rebuke from Congress, which passed a measure proposing a review of the way the advice informing the guidelines is compiled. It referred to “questions … about the scientific integrity of the process”. The scientists reacted angrily, accusing the politicians of being in thrall to the meat and dairy industries (given how many of the scientists depend on research funding from food and pharmaceutical companies, this might be characterised as audacious).

Some scientists agree with the politicians. David McCarron, a research associate at the Department of Nutrition at the University of California-Davis, told the Washington Post: “There’s a lot of stuff in the guidelines that was right 40 years ago but that has been disproved. Unfortunately, sometimes, the scientific community doesn’t like to backtrack.” Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, was blunter, calling the new guidelines “an evidence-free zone”.

The congressional review has come about partly because of Nina Teicholz. Since her book was published, in 2014, Teicholz has become an advocate for better dietary guidelines. She is on the board of the Nutrition Coalition, a body funded by the philanthropists John and Laura Arnold, the stated purpose of which is to help ensure that nutrition policy is grounded in good science.

In September last year she wrote an article for the BMJ (formerly the British Medical Journal), which makes the case for the inadequacy of the scientific advice that underpins the Dietary Guidelines. The response of the nutrition establishment was ferocious: 173 scientists – some of whom were on the advisory panel, and many of whose work had been critiqued in Teicholz’s book – signed a letter to the BMJ, demanding it retract the piece.

Publishing a rejoinder to an article is one thing; requesting its erasure is another, conventionally reserved for cases involving fraudulent data. As a consultant oncologist for the NHS, Santhanam Sundar, pointed out in a response to the letter on the BMJ website: “Scientific discussion helps to advance science. Calls for retraction, particularly from those in eminent positions, are unscientific and frankly disturbing.”

The letter lists “11 errors”, which on close reading turn out to range from the trivial to the entirely specious. I spoke to several of the scientists who signed the letter. They were happy to condemn the article in general terms, but when I asked them to name just one of the supposed errors in it, not one of them was able to. One admitted he had not read it. Another told me she had signed the letter because the BMJ should not have published an article that was not peer reviewed (it was peer reviewed). Meir Stampfer, a Harvard epidemiologist, asserted that Teicholz’s work is “riddled with errors”, while declining to discuss them with me.

Reticent as they were to discuss the substance of the piece, the scientists were noticeably keener to comment on its author. I was frequently and insistently reminded that Teicholz is a journalist, and not a scientist, and that she had a book to sell, as if this settled the argument. David Katz, of Yale, one of the members of the advisory panel, and an indefatigable defender of the orthodoxies, told me that Teicholz’s work “reeks of conflict of interest” without specifying what those conflicts were. (Dr Katz is the author of four diet books.)

Dr Katz does not pretend that his field has been right on everything – he admitted to changing his own mind, for example, on dietary cholesterol. But he returned again and again to the subject of Teicholz’s character. “Nina is shockingly unprofessional … I have been in rooms filled with the who’s who of nutrition and I have never seen such unanimous revulsion as when Miss Teicholz’s name comes up. She is an animal unlike anything I’ve ever seen before.” Despite requests, he cited no examples of her unprofessional behaviour. (The vitriol poured over Teicholz is rarely dispensed to Gary Taubes, though they make fundamentally similar arguments.)

In March this year, Teicholz was invited to participate in a panel discussion on nutrition science at the National Food Policy conference, in Washington DC, only to be promptly disinvited, after her fellow panelists made it clear that they would not share a platform with her. The organisers replaced her with the CEO of the Alliance for Potato Research and Education.

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One of the scientists who called for the retraction of Nina Teicholz’s BMJ article, who requested that our conversation be off the record, complained that the rise of social media has created a “problem of authority” for nutrition science. “Any voice, however mad, can gain ground,” he told me.

It is a familiar complaint. By opening the gates of publishing to all, the internet has flattened hierarchies everywhere they exist. We no longer live in a world in which elites of accredited experts are able to dominate conversations about complex or contested matters. Politicians cannot rely on the aura of office to persuade, newspapers struggle to assert the superior integrity of their stories. It is not clear that this change is, overall, a boon for the public realm. But in areas where experts have a track record of getting it wrong, it is hard to see how it could be worse. If ever there was a case that an information democracy, even a very messy one, is preferable to an information oligarchy, then the history of nutrition advice is it.

In the past, we only had two sources of nutritional authority: our doctor and government officials. It was a system that worked well as long as the doctors and officials were informed by good science. But what happens if that cannot be relied on?

The nutritional establishment has proved itself, over the years, skilled at ad hominem takedowns, but it is harder for them to do to Robert Lustig or Nina Teicholz what they once did to John Yudkin. Harder, too, to deflect or smother the charge that the promotion of low-fat diets was a 40-year fad, with disastrous outcomes, conceived of, authorised, and policed by nutritionists.

Professor John Yudkin retired from his post at Queen Elizabeth College in 1971, to write Pure, White and Deadly. The college reneged on a promise to allow him to continue to use its research facilities. It had hired a fully committed supporter of the fat hypothesis to replace him, and it was no longer deemed politic to have a prominent opponent of it on the premises. The man who had built the college’s nutrition department from scratch was forced to ask a solicitor to intervene. Eventually, a small room in a separate building was found for Yudkin.

When I asked Lustig why he was the first researcher in years to focus on the dangers of sugar, he answered: “John Yudkin. They took him down so severely – so severely – that nobody wanted to attempt it on their own.”

Ian Leslie, the author of Curious: the Desire to Know and Why Your Future Depends On It, is a regular contributor to the Long Read. Twitter: @mrianleslie

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Sweet Conspiracy

Your complete source for natural health and wellness

Hungry, Jenny ate four teaspoons of peanut butter straight from the jar. Within minutes she became hyperactive. Sound familiar? In these four teaspoons of grocery store-bought peanut butter, Jenny just ate one whole teaspoon of sugar.
A sugar-induced epidemic may have already begun: More than two million Canadians now have diabetes, a leading cause of death by disease in this country. By 2010, that number is estimated to rise to three million (Canadian Diabetes Association). Risk factors for type II diabetes obesity and impaired glucose tolerance suggest a link to excess sugar consumption.

What is Sugar?

Sugar is a carbohydrate, which is one of the three macronutrients we need to live (the other two are protein and fat). Not limited to just white table sugar, there are actually six types: fructose, galactose, glucose, lactose, maltose and sucrose.

If the only sugar we consumed were in nutrient-dense whole foods, such as fruit and vegetables, we’d all be fine. However, eating too many refined or concentrated sugars such as brown sugar, corn syrup, processed honey and white table sugar, all of which lack any nutrients, can cause health problems.

Why Else is Sugar Bad for Me?

Eating too much sugar can compromise your immune system. According to Kenneth Bock, MD, an expert in nutritional and environmental health in New York, two cans of soda pop (which together typically contain 18 to 22 teaspoons of sugar) reduce the efficiency of white blood cells (an integral part of your immune system) by 92 percent an effect that lasts up to five hours.

Your body quickly absorbs refined sugar into your bloodstream, which causes your pancreas to rapidly release the hormone insulin to normalize blood sugar levels. In turn, this can cause blood sugar to suddenly drop. To compensate, your adrenal glands release high levels of another hormone, cortisol, which puts your body in high-stress mode. This constant stress from high sugar intake leads to early menopause, adult-onset diabetes (type II), hypoglycemia and chronic fatigue.

And consider this: your body draws from its nutrient reserves to metabolize sugar. Depleted nutrient reserves leave your body unable to metabolize fatty acids and cholesterol, which could put you at risk for a range of diseases from cardiovascular disease to adult-onset diabetes.

Worse, children are the biggest consumers of sugary foods, and they are eating them at a time when their brains and bodies are growing rapidly and they need a nutrient-dense diet for proper physical and mental development.

Should I Still be Concerned About my Sugar Consumption?

Most naturally sweet whole foods don’t really contain much sugar. A cup of strawberries, for example, contains about one-sixth the sugar of a can of cola.

But unless you eat a diet made entirely of whole, unprocessed foods, you’re probably eating too much sugar. Sugar in its many forms is added to virtually every packaged food product and not just the sweet stuff. If you eat one serving of fruit-flavoured yogurt, even some natural varieties, you’ve probably used up your day’s sugar allowance.

Don’t be fooled by the ingredients list. By law, a food manufacturer has to list the ingredients in a product by weight. The first ingredient listed is the predominant ingredient. For example, three different sugars in the middle of the list appears as if the product contains not much sugar. But grouped together, sugar would be the first ingredient.

Is there a Safe Amount of Sugar?

The average Canadian consumed about 40 kilograms (90 pounds) of refined sugar in 2000, according to Statistics Canada (CANSIM II, “Per Capita Consumption of Major Food Groups,” January 2002). Ideally, you should eliminate all refined, concentrated sugar from your diet. If you can’t completely cut out sugar, try not to eat more than five teaspoons a day or get more than five per cent of your daily calorie intake (assuming a 2,000 calorie diet) from all types of sugar, whichever number is lower.

To find out how much added sugar you’re consuming, keep a food diary for one week. From the labels of the foods you eat, note the sugar content in grams. At week’s end, take the total number of sugar grams and divide it by 4.2 to get your weekly sugar intake in teaspoons (4.2 grams of sugar is approximately one teaspoon). Then divide that number by seven to get your daily sugar consumption.

How do natural sweeteners like honey stack up?

Some natural sweeteners organic blackstrap molasses, unprocessed honey, fruit juice and dried natural sugar cane juice (such as Rapadura and Sucanat), for example contain low levels of nutrients such as B vitamins and iron, calcium and potassium. But these natural sweeteners are still highly concentrated sugars and have a similar effect on your body.

A great choice is the herb stevia (Stevia rebaudiana). Not only is stevia safe and calorie-free, but one study also shows that it may lower blood sugar levels in diabetics by helping to regulate pancreatic function. Stevia also has antimicrobial properties and might help the body fight off colds and flu.

What About Aspartame and Saccharin?

Don’t switch from natural sugar to sugar-free substitutes. Many wholistic doctors agree that artificial sweeteners are more unhealthy than sugar. Enough evidence exists from small studies and doctors’ experiences to cause concern about aspartame. Possible links exist between aspartame and birth defects, headaches, brain tumours and aggravation of mood disorders.

Saccharin was found to produce urinary bladder tumours in male rats. Until recently, all products that contained saccharin had to carry a warning, “Use of this product may be hazardous to your health.”

After a lifetime of consuming refined sugar, many North Americans are addicted and will do anything to get a fix even compromise their health. It’s time to reduce our sugar consumption and take control of our health.

Sugar Cravings?

Choose from these natural, unrefined sweeteners for the occasional sweet dish:

• stevia
• organic maple syrup
• organic blackstrap molasses
• powdered dates
• unpasteurized honey
• natural dried (granulated) sugar cane juices such as Rapadura and Sucanat
• fresh and dried fruits
• fruit juices
• brown rice syrup

Sugar-Pop Snapshot

The average Canadian drank 113 litres of soft drinks in 2000 close to one can of sugar-filled pop a day.

Source: Statistics Canada, CANSIM II, “Per Capita Consumption of Major Food Groups,” January 2002

Name That Sugar

In addition to fructose, galactose, glucose, lactose, maltose and sucrose, sugar goes by many other names. For a comprehensive list of sugar pseudonyms, see Health Hazards of White Sugar by Lynne Melcombe (alive Natural Health Guide, 2000), available through your local health food store or alive Books at 1-800-663-6513.

• barley malt
• brown, golden or yellow sugar
• caramel
• corn syrup
• dextran, dextrose
• diastase, diastatic malt
• ethyl maltol
• golden syrup
• malt syrup, maltodextrin, maltose
• mannitol, sorbitol, xylitol
• sorghum, sorghum molasses

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