Late Night Musings on the Origin of Life

The conventional view of the origin of life is that some combination of simple-enough chemicals was able to catalyze the synthesis of the same chemicals, and that was enough to begin a process of evolution that became more efficient as it became more intricate.  One problem with this idea is that no such self-reproducing combination of chemicals is known, or has ever been synthesized or engineered.  The simplest known self-replicating systems are enormously complex compared to anything that might plausibly have arisen by chance.  Improbable as is the conventional view, the alternatives are far stranger.

The paradox in a nutshell

Consider what we might deduce from these three facts.

  1. The oldest fossils are almost as old as the earth.  So life must have appeared on earth as soon as the earth was cool enough to have liquid water.
  2. Biochemists have devoted a great deal of ingenuity to the task of creating a molecule or network of molecules that can self-reproduce, when immersed in a bath with appropriate chemical feed-stock.  They haven’t made it to first base.
  3. All life on earth is related, all descended from the same proto-cell.

When we think of the transition from non-living matter to living systems, we imagine some network of molecules that formed a self-catalyzing loop.  Typical bio-molecules have thousands of carbon atoms arranged in a precise shape and structure that could never have come about by chance.  The earliest proto-living system did not have to be efficient, because there was no competition, but it had to be simple, because once you start combining more than a dozen or so carbon atoms together, the number of ways they can be linked is so large that any one combination would not be expected to appear even once in all the vast oceans over many millions of years.  So what we need is a system of molecules, for example A, B and C are all simple enough to have arisen by chance, and A makes it more likely that common molecules in the neighborhood will come together to form B, and B likewise catalyzes C, and C increases the probability of formation of A.

We think it must have happened somewhere, sometime.  In the early days of biochemistry, it was common to assume that this first step with self-replicating organic molecules must be easy.  In 1953, Stanley Miller and Harold Urey passed sparks through a tank of water, ammonia and methane, simulating the earth’s early atmosphere in the presence of lightning, and he found that some common organic molecules were created, including some amino acids.  Bingo!  Harlow Shapley wrote in Of Stars and Men (1957),

No longer is the origin of life a deep mystery.  Supernatural “intervention” in the biochemical development which we call life is not required.  Natural operations, most of them already known, will suffice.  We have bridged, at least provisionally, the gap between life and the lifeless.  The microbiologist probing down from cells toward the inanimate and the chemist moving up from atoms toward the animate are practically in contact.  Much detailed work, however, remains to be done.

Much detail, indeed.  We realize now that there is a mystery.  The gap between non-living and living systems seems wider now that we’ve spent 60 years trying to bridge it.  For comparison, the number of people playing with cellular automata is much smaller, but the self-replication problem has been solved handily in that context.  Cellular automata are “toy worlds” that obey simple, made-up rules, for propagating from one generation to the next.  The most famous is John Conway’s Game of Life, and here is a self-replicating pattern that works with those rules.

So Fact #1 would lead us to expect that maybe the first steps in the formation of life were easy and probable, while Fact #2 implies the opposite.

Fact #3 suggests maybe life appeared only once, adding more weight in favor of “difficult and improbable”.  Or maybe life evolved in many places at many times, but one of these simply out-competed the others, and so descendents of just this one life remain on earth today.  This is potentially the biggest loophole in my thesis, so I want to dwell on it for a few paragraphs.

 

All life on earth has a common ancestor.  Does this mean that life arose only once?

We know that all life on earth has a common ancestor because there are many things that all living cells have in common with each other, and some of them are quite arbitrary.  One example is the genetic code, which seems to be composed of three-letter “words” for specifying amino acids (= protein building blocks) which appears to be as arbitrary as any association between letters and meaning in a human language.  Another example is the fact that all biological amino acids are left-handed, and all nucleic acids are right-handed.  In other words, these molecules are different from their mirror images, and we know that a mirror image of all of life’s chemistry would behave identically to life as we know it (provided that all the molecules were mirror-imaged).  Inorganic chemical processes always create left- and right-handed molecules in equal numbers, but biochemical processes always create exclusively one handedness only.

I enjoy thinking about LUCA, the Last Universal Common Ancestor, a single cell existing perhaps 3 billion years ago from which you and I and every mushroom and mosquito and all life on earth has descended.  Strange as it seems, there is no alternative hypothesis that isn’t far stranger.

If we think life evolved from molecule to primitive cell within 300 million years, that suggests that there has been ample time and opportunity for life to have arisen in other times and places, before and since.  Why wouldn’t descendants of these other origins of life appear somewhere on earth today?

We are used to thinking in terms of varieties that vie for a niche, and one does a better job than the other, and so the former drives the latter to extinction and takes over.  It has been argued that once Life I got a head start, it might be so efficient that newly-formed Life II and Life XIX would not have a chance of invading its territory.

I am not convinced this is true.  Life forms that are very similar may vie for the same niche:  they are attacked by the same predators, get the same diseases, and rely on the same resources.  But why would Life II be vulnerable to Life I if the two were very different?  There is a mathematical theorem from evolutionary theory (Gause’s Law), purporting to prove that two varieties cannot coexist stably in the same niche.  Whichever reproduces faster will drive the other to exinction.  While this is true in theory, it seems that in richly productive ecosystems, the niches are sliced awfully thin, so that in tropical rainforests and coral reefs (the two most prolific ecosystems in the world), many species with very similar characteristics manage to co-exist and thrive together for long periods without getting in each other’s way.

How much more true would we expect this to be if two forms of life had an entirely different chemical basis!  Life II might be based on carbon chemistry, but using neither proteins (amino acids) for signaling and as workhorse molecules, nor DNA (nucleic acids) for information storage.  Life I would not eat Life II, because Life I lacks the enzymes necessary to digest Life II.  Even if it could be digested, it is unlikely that the chemical constituents of Life II would be useful to Life I.  We (Life I) can eat sugars and proteins, but we can’t digest diesel oil or polyethylene, even though these feedstocks contain chemical energy in abundance that could, in theory, be useful to us.

In what sense would Life I and Life II be competing at all?  Only in the sense of both needing water and an energy source – say mineral compounds at undersea vents, or sunlight.  Certainly it is probable that Life I or Life II might be much the more efficient at converting energy into biomass, and at rate of reproduction; still It is not at all clear that Life I and Life II would not be able to stably co-exist, or that one form would necessarily drive the other to extinction.

 

Life before LUCA

The (ultimate) energy source for most life today is sunlight.  Furthermore, the earliest fossils that we have are the blue-green algae (cyanobacteria), the alchemists that alone are able to capture the energy of the sun and store it as chemical energy.  This is the chemistry of chlorophyl and photosynthesis, and, as far as we know, it evolved only once.  The cyanobacteria had a monopoly on the process for more than 2 billion years, until they colonized early eukaryotes (complex nucleated cells) and were tamed by them as chloroplasts, which remain to this day the “green” in green plants, and the energy factories for everything from moss to Giant Sequoias.

And yet the biochemistry of photosynthesis is far too complex and sophisticated for us to imagine that cyanobacteria evolved first from non-living matter.  There must have been some intermediate life form with lower complexity, and we are not surprised that it left no fossil imprints.

There are many competing theories, many scenarios for the way in which life might have arisen from non-living matter.  My favorite, explored with a masterful knowledge of chemistry and a creative imagination comes from Nick Lane.  My point is that all these are descriptive, and lack detail.  There is nothing like a proof or demonstration that life could have arisen in the brief time in which we know life did appear, and, of course, there has been no success engineering a chemical system capable of reproduction in the laboratory, let alone a system simple enough that it might plausibly have arisen by chance.

 

If anything is worthy of cosmic wonder, surely it is this

Where all this is headed – the epiphany that started me writing this essay – is the improbability of the first life forms, the bridge that carried nonliving matter into the realm of the living.

(This is the original “chicken and egg” problem, and it carries us to the brink of Creationism.   To offer “God did it” as an explanation seems to me to offer no advantage compared to the simpler statement, “we don’t know” or “it is an enduring mystery”.  On the other hand, I think that evolutionary scientists have been less than honest in acknowledging the vulnerabilities and mysteries in the evolutionary process, in part because they have felt the need to take a hard line against attacks from fundamentalists.)

James Russell Lowell, the 19th Century transcendental poet, wrote

We pass unconscious o’er a slender bridge,
The momentary work of unseen hands
Which crumbles down behind us.  Looking back,
We see the other shore, the gulf between,
And, marveling how we won to wear we stand,
Content ourselves to call the builder Chance.

So I look as an (independent, heretical) scientist on the evidence, and I ask: what could explain the highly-improbable appearance of living forms on earth, so soon after the early earth cooled sufficiently to make life possible?

One answer is an extra-terrestrial origin for life.  Perhaps the earth was deliberately seeded by some advanced civilization (after all, the Universe was already 9 billion years old, ⅔ its present age, when sun and earth were born)…this leads to the Fermi Paradox and other mysteries.  Or else there are bacterial spores sufficiently resilient that they can ride a rock ejected from a planet by violent volcanism, then survive dormant for millions of years in interstellar space, and survive (yet again) the heat bath of re-entry into a planetary atmosphere.  The spores then detected water and hospitable temperatures, and they awakened from a long, long sleep.

Unlikely?  As I see it, the alternatives are Little Green Men or mysticism.  Panspermia is the hypothesis of a single origin for all life in the universe, a recognized and legitimate hypothesis (if not dignified by the Science establishment) with roots that go back to Anaxagoras, and a following that includes no less a luminary than Francis Crick.  Panspermia does not solve the riddle of the origin of life, but only pushes the question back to a previous planet in a previous epoch, but the available space and time for life to appear is vastly increased.

…or maybe the biochemists have overlooked something that’s not so difficult, and the origin of that first cell is not as improbable as it seems….or maybe there is a propensity for life that is woven into the behavior of matter, and shielded from our view by what Quantum Mechanics calls irreducible randomness, electrons and protons are biasing their trajectories in tiny ways that aim toward life, perhaps toward awareness.  The boundary between science and speculation is where I love to hang out.

 

pf button Late Night Musings on the Origin of Life

Less meat, More life

Vegetarians outlive non-vegetarians by several years.  The result may be largely (or entirely) due to lower weight, and higher consumption of fresh vegetables and fruits, rather than to an adverse effect of meat per se.   Vegans have an even greater advantage than vegetarians who eat dairy and eggs, and again vegan weight trends even lower than other vegetarians.  It goes without saying that in this context a longer life goes hand-in-hand with a healthier life. Rates of diabetes, heart disease, and selected cancers are much lower in vegetarians, and yet lower in vegans.  

 

I have been a vegetarian since 1973, motivated (now) by years of habit and (then) by a hypnotic suggestion from my first yoga teacher.  One evening, about five months into my discovery of yoga, I was lying on the floor in savasana (deep relaxation) when the revered and beloved voice of my teacher suggested to the class that perhaps we might find our practice leading us to eat less meat.  I was startled awake, and sat bolt upright.  In previous weeks, she had suggested cutting back coffee and alcohol and TV and marijuana (this was Berkeley!) and cigarettes—it all went down smoothly because I had never been attracted to any of those things.  But what could she be thinking, classing meat with intoxicants and mind-altering drugs?  I had never questioned that a diet that was ultra-high in protein would keep me strong and healthy.  The phrase “new age hocum” hadn’t been invented yet, but those are just the words for which my mind was searching.

Six weeks later, I was a vegetarian.  My teacher’s hypnotic suggestion awakened my discomfort with surrogate killing of animals.  It had nothing to do with science.  Now there is evidence linking low meat consumption with longevity, but much less was known 40 years ago, and even that was unknown to me.  I became aware that I was uncomfortable eating animals, and I have never looked back.

Years later, I raised my two daughters to eat whatever they wanted to eat, and was secretly delighted when, as pre-teens, they each decided that (though they enjoyed the taste of meat), it was too unsettling for them to think of the animal who died to become their meal.  Both daughters have maintained their vegetarianism into adulthood, though everything else about them has changed.

As a public health advocate, I have been very cautious about suggesting vegetarianism to anyone.  I am still wary that my own habits and emotions may be affecting my judgment.  But more studies than ever support the role of vegetarianism in a life extension plan, and prompted by a recent ScienceDaily article, I’ll look at vegetarian diets in this week’s column.

 

Seventh Day Adventist Study

Studying the long-term consequences of a vegetarian diet is complicated by the fact that vegetarians are far from a random sample.  There are a lot more women than men, more liberals than conservatives, more environmental awareness, more health-consciousness, more propensity to exercise among vegetarians [2012 Gallup poll].  More surprisingly, vegetarianism is associated with fewer years of education, and there are a lot more Baby Boomer vegetarians than among younger generations.

41% of Seventh Day Adventists call themselves vegetarians, compared to 5% of Americans generally.  This makes SDA an ideal population to a study the effects of a vegetarian diet holding other factors fairly constant.  Vegetarianism among SDA cuts across racial and socio-economic divisions.

Consistent with past studies, the SDA study gave vegetarians 3 extra years of life.  Note that SDA men already live 7 years longer than other Americans (4½ years for women).  So the vegetarian advantage in SDA studies is on top of a large head start.  7 years is big! comparable to the difference between Japan (world’s highest life expectancy) and Mexico (representative of the worldwide average, outside Africa which is shockingly low) [Wikipedia list]

Benefits were reported for for heart disease (especially) and selective cancers, cancers of the digestive tract in particular.  Past studies have found that cardiovascular mortality is 24% lower among vegetarians.

Gary Fraser, an MD-PhD cardiologist at SDA-affiliated Loma Linda University, has written a great deal on the health benefits of vegetarian diets.  Here is a chart from his 2009 review of SDA and other data:

 

Diet group BMI rel incidence
of Diabetes
rel incidence
of Hypertension
Nonvegetarian 28.26 1.00 1.00
Semivegetarian 27.00 0.72 0.77
Pescovegetarian 25.73 0.49 0.62
Lactoovo-vegetarian 25.48 0.39 0.45
Vegan 23.13 0.22 0.25

Look at the diabetes rates for vegans compared to non-vegarians – only 1 / 5th as high!  Diabetes contributes to all the diseases of old age.

But look at the first column, BMI.  Non-vegetarians in the study had BMI of more than 28, compared to 25 – 26 for vegetarians and 23 for vegans.  Differences of this order could easily account for the entire 3 year life expectancy advantage [Oxford study, 2009].  There are theoretical reasons why vegetable protein might be helpful in modulating the metabolism in ways that keep weight down and insulin sensitivity up.

The vegetarian advantage appears in a much reduced incidence of early death, most apparent between ages 50 and 60.  (For younger decades, the death rate for both vegetarians and meat eaters is too low to make much difference, and at older ages, the advantage of vegetarianism is gradually overtaken by genetic and other factors affecting longevity.)

Findings about the advantage of fruit and (especially) green vegetable consumption should come as no surprise.  More interesting is a paper from the SDA study devoted just to nuts.  Eating a lot of nuts contributed to a lower risk of obesity and, to a lesser extent, metabolic syndrome.  Peanuts were not as helpful as other nuts.  Personally, I find that nuts are a convenient and tasty component of a low-carb vegetarian diet.

 

The Bottom Line

If you are inclined to a vegetarian diet for poliitcal or environmental or philosophic or religious reasons, then by all means enjoy the satisfaction of knowing that you are doing your body a favor, and your diet is conducive to health and longevity.  If your diet includes meat, keep in mind that the most important things you can do are to keep your weight down and expand on vegetables, nuts and fruits, with leafy greans at the top of the list.  If you are contemplating a change, I suggest that you try a vegetarian eating style for a week or even for a day at a time as a way to expand your culinary horizons and explore how it feels to you.

pf button Less meat, More life

V.N. Anisimov: Russian Optimist on Longevity

Last March, I wrote a column entitled Reality Check, featuring the work of Stephen Spindler.  Spindler is a veteran researcher at UCRiverside, and perhaps the world’s foremost expert in the design and execution of longevity studies in mice.  But Steve is a glass-half-empty kind of guy.  And ever since I wrote that column, I’ve been thinking that I need to write about Spindler’s opposite number in Russia:  Vladimir Anisimov is a veteran gerontologist at the Petrov Institute in St Petersburg, who has also been testing longevity potions on mice through a long career.  Anisimov is a glass-half-full kind of guy.  His best contribution to anti-aging medicine may be epithalamin, a treatment that has been hiding in plain sight for over thirty years.

An innovator with a deep knowledge of biochemistry, Anisimov has published theoretical as well as practical science.  His lab has tested biochemical ideas about aging, as well as doing many studies on genetics and longevity in rodents and flies.  He has reported and summarized results of other Russian labs in English-language journals.

Some of Anisimov’s findings are well-known to me, and therefore to followers of this blog and of my Aging Advice web site.  Metformin reduces mortality and slashes cancer risk in people who take it as a medication for diabetes.  Metformin increases life span of ordinary non-diabetic mice.  Anisimov thinks it will do the same for non-diabetic humans, and I agree it’s a good bet.  Melatonin, the hormone that regulates our daily cycle, is also found to prolong life span in mice.   Melatonin in the blood is very sensitive to light exposure, and melatonin disappears with the dawn’s early light   Anisimov found that sleeping in total darkness is better for longevity than exposure to light during the night.  Here are two reviews by Anisimov of mostly Russian work on life extension with melatonin [2003, 2006].

(Unrelated to melatonin and to Anisimov: A recent study also suggests sleeping in the cold helps preserve insulin sensitivity.)

Another of Anisimov’s lines of research is less well-known to me, and I report here my first impressions.  He has worked with “short peptides”, strings of less than 10 amino acids, that can act as signals or switches that control body chemistry globally.  Short peptides are small enough to pass easily through the skin or through the blood-brain barrier.  Unlike full-size proteins, short peptides tend to resist dismemberment by stomach enzymes.  Carnosine and carnitine are familiar examples of di-peptides, consisting of 2 amino acids.

Here’s the theory:  We know that gene expression is quite different in old and young people.  In the literature, you find various interpretations and explanations why this might be true.  But my interpretation is clear and simple:  The body times its life cycle using gene expression.  When we’re young, we express genes that make us grow.  When we’re middle-aged, we express genes that keep us healthy.  When we’re old, we express genes that destroy us.

“Gene expression” is the translation of DNA into proteins.  Proteins are the signals and the workhorses of body chemistry.  The translation is well understood since Francis Crick discovered the Genetic Code in the 1960s.  But the language for determining which gene gets expressed when is apparently much more complicated, and it is just beginning to be decoded in the 21st Century.  This is the science of epigenetics.

Among the signals that can locate a particular stretch of DNA, and turn it ON or OFF are short stretches of RNA called pi-RNAs, methyl transferases and histone de-acetylases.  (I’m sorry to throw biochem jargon at you, but I’m excited to have just barely begun to educate myself about the fundamentals of epigenetics with a Coursera course this spring.)  But the point is that these short peptides that Anisimov has been studying for 20 years work also as gene promoters and repressors – epigenetic signals that are more specific than the methyl transferases and less specific than pi-RNAs.  Apparently they can affect whole categories of genes [ref].

Here’s a paper in which Anisimov summarizes 35 years’ experience with animal experiments, and some tantalizing human results as well.  (One of the differences in Russian bio-medicine, for better and for worse, is that regulations about experiments on humans are more relaxed than in the US.)   Here’s a table summarizing results in mice and rats.  (As usual, life extension in flies is more dramatic, but less indicative of human benefits.)  As you can see, this is a science that goes back to the 1970s, when the top two preparations were purified from epithalamus and thymus glands.

Anisimov table of short peptides V.N. Anisimov: Russian Optimist on Longevity

The thymus is a gland in the upper chest that trains the immune cells in our blood to attack invading cells, but to lay off our own body’s cells.  As we get older, the thymus shrinks, and I believe this to be a basic cause of aging immune function, auto-immune disease, and increased susceptibility to infection.  Thymalin was found to stimulate thymus re-growth and to rejuvenate immune function.

Epithalamin is also called epitalon or epithalon, and was discovered in extacts from a region of the brain called the epithalamus.  This region contains the pineal gland, or “third eye”, which controls wake/sleep cycles and is the body’s source of melatonin.  Like thymalin, epithalamin is a string of four amino acids.  Thymalin generated excitement in the 1980s, until epithalamin stole its thunder.  Not only did it extend life more consistently, but its effect on thymic growth was found to be superior to thymalin.

In the table, epithalamin has been the best-studied short peptide, and it has the best record for life extension in rodents.  In a separate table, the same paper shows that epithalamin and thymalin suppress cancer in rodents.  There is also evidence of large reductions in mortality when epithalamin was given to older human subjects:

Anisimov short peptides human mortality V.N. Anisimov: Russian Optimist on Longevity

In addition, it has recenty been reported (2003, 2004) that epithalamin is a telomerase activator.  Skeptics (Spindler in particular) point out that caloric restriction is such a strong influence on life span that many treatments will appear to show benefit only because they affect appetite.  Some of the studies do measure food intake, and find that epithalamin is able to increase lifespan without decreasing food consumption.

(Epitalon is available commercially, but not from most supplement sources.  Recommended dosage is usually less than 10mg, but experience with different dosages is very limited.)

 

Reference: a crash course in mid-brain anatomy

Here’s a picture of the human brain, courtesy of Wikipedia.  The mid-brain is the endocrine function, where computations made with neurons are translated into prescriptions for internal secretion.

Mid brain V.N. Anisimov: Russian Optimist on Longevity

The epithalamus is shown in cherry.  It includes the pineal gland, the so-called “third eye” which is responsible for the body’s light-sensitive clock, and where melatonin comes from.  The hypothalamus is shown in lime.  It includes various “nuclei”, notably the suprachiasmatic nucleus, which is the closest thing science has found to a developmental clock.  The pituitary is also part of the hypothalamus, and secretes hormones involved in the life cycle and the menstrual cycle: HGH, LH, FSH, TSH and sex hormones.

Conclusions

All of this looks so promising that I wonder why there hasn’t been more follow-up, and why American researchers haven’t built on the Russian results.  Russian science tends to be more adventurous than American science.  That doesn’t mean they make more mistakes.  The problem with American science is that it is too rigidly institutionalized and controlled within an establishment.  It is usually not possible to get funding to ask a question to which you do not already know the answer.  So the mistakes of American science are more likely to be under the header “confirmation bias”, while Russian science is more likely to be offering results that may not pan out.  This seems to be a well-established field, with positive results that have been affirmed over decades in different labs with flies, rodents, and humans.  My web search identified no dangers or reports of toxicity.  I’d say it’s high time the American and European gerontology communities picked up this thread.  In the mean time, please comment if you have any experience with epitalon or other short peptides.

pf button V.N. Anisimov: Russian Optimist on Longevity

Human Mortality, Individual and Collective

It has been a major triumph of human civilization: Never before in evolutionary history has a species lifted itself from Darwin’s Struggle for Existence, and created a safe, secure environment in which a majority of individuals may expect to live out a full life expectancy and die of old age. You and I take for granted that aging is the greatest hurdle that we face in our quest to live a long, long time. Let’s hope this is true.

Let’s do more than hope. Let’s remember that aging evolved in order to keep ecosystems in balance, to keep populations from outgrowing their resources. If we are at the forefront of the movement to extend individual life span, we must also be at the forefront of a movement to lower birth rates and shrink the human footprint.

Me, my and mine: The Human Species and the Terrible Twos

Before we learned empathy, before we learned to share and to wait our turn, before we learned to provide for others and to trust that our needs would be provided in turn—we were Terrible Two-year-olds. Everything was me, my and mine.

Before humanity, Gaia was a diverse and wondrous beast, a many-headed Hydra, with different local faces in mountain and forest and desert and ocean environments, every acre a unique ecosystem.

Henry David Thoreau spoke of teaching the earth to say “beans” instead of “grass” — “this was my daily work.” The history of humanity on this planet has been to divert the Earth’s primary productivity from the diverse cycles and epicycles in the tangled bank that is nature, to align the primary productivity in the service of man, to feed and clothe and house us, to provide our comfort and transportation and amusement.

As humans spread out of Africa some 60,000 or was it 200,000) years ago, every place that we appeared, the charismatic megafauna would disappear, and humans would replace them at the top of the food chain. Giant bears in Europe, Giant Sloths in South America, Mastodons and Sabre Tooth Tigers in North America, Great Awks in Iceland, 7-foot Kangaroos and 3-ton Wombats in Australia, 8-foot Moas in New Zealand (the original Big Bird). All the largest animals that thought they were safe from predation succumbed to the chiseled flint spearheads and the clever tricks and traps of small bands of humans. Ecosystems were made over in our service.

For thousands of years, we humans thought only of me, my and mine. We understood that as we domesticated the planet there would be victims. There are winners and losers in the game of life. It is our mission, our destiny to make sure we are among the former.

Recent centuries have seen an acceleration of this process, impressive increases in the conversion of grass to beans. Hunting and gathering yielded to agriculture, then factory farms. Monoculture has replaced the tangled bank.  Greater triumphs for humanity, greater losses for the lower plants and animals that we displace.

Blowback

We all live in artificial environments, “Little we see in nature that is ours,” wrote Wordsworth over 200 years ago, and I daresay he never saw Walmarts or even Manhattan. We take a moment to remember the plight of the dying birds and the frogs, the poor frogs – the world’s amphibian populations have been disappearing at the rate of more than 3% per year. We miss nature, we truly do, but we imagine all the same that their loss is our gain. Man is no longer dependent on the ecosystem that birthed us. We can live in an engineered world. We will cover the Earth with farms and factories and housing, and human life will go on, even if what we know as Nature is dead as a Dodo.

What if it isn’t true? What if human life is more dependent on a functioning ecosystem than is apparent? We are already coping with a precipitous decline in pollinating insects by renting out mobile beehives to our farmlands. We don’t really know to what extent our farms are dependent on the ambient ecology. Bacterial communities recycle carcasses into nutrients. Wetland ecologies purify water. Oceans buffer our atmosphere.

 Human Mortality, Individual and Collective

Could you kindly rephrase that in equivocal, inaccurate, vague, self-serving and roundabout terms we can all understand?

 

California grows half of the produce consumed in the United States, and continues to do so by mining a fossil water table which is down 40 feet in the last 40 years. The American Midwest is the breadbasket not just for the US of A, but for much of the world; and there a rich layer of topsoil, laid down over tens of thousands of years, is being washed into the Mississippi in a few decades.

Putting a dollar value on “ecosystem services” may be an absurdity, but here is a study that sought to catalog some of the value of Nature, and stopped when they got to a number that was twice the economic output of the entire world.

We don’t know how much we can grow or how many people we can support on this planet sustainably, because we’ve never tried. But there has been one small-scale experiment that may be instructive. In the late 1980s, visionary scientists constructed Biosophere II [link] in the Arizona desert. It was conceived as a self-contained microcosm of Planet Earth (re-named “Biosophere I”), complete with farmlands, forest, wetlands, a desert, a miniature ocean with coral reef and a tropical jungle modeled on the Amazon – all in an enclosed dome that covered p acres. The biological community was engineered to be a closed, self-sufficient artificial ecosystem, recycling oxygen with its plants and purifying water in its wetlands. There was solar energy aplenty.

330px Wiki bio2 sunset 001 Human Mortality, Individual and Collective

The experiment was a disaster. Atmospheric oxygen was permitted to decline to 2/3 of its ambient value before the project doctor (well-known and well-loved by many of us in the life extension community) rebelled and insisted on fulfilling his Hippocratic oath. Neither was the community ever self-sustaining in food or clean water. The residents/scientists/pioneers had no idea what they had committed to, and relations became contentious when the basics of life were in short supply. Stories survive of smuggled food, fistfights, and residents who took survival into their own hands, breaking windows to permit air exchange.

Resource Wars

If it becomes clear that the planet cannot support all of us as resources begin to be in short supply, we may imagine some of the diverse responses of people and governments. For many people, hardship brings out our noblest altruistic nature. For others, there will be food fights and resource wars. Me, my and mine. Governments have already offered us hints about the lengths to which they are willing to go to “preserve order” in a crisis.

Healthy, caring and progressive human minds do better not to think about such things, as their contemplation can make us feel helpless and drag us into depression. Joanna Macy has devoted her career to helping us keep our sanity as we advocate for peace and environmental sanity.

Latency

Chemists call it “latency”. Physicists say “hysteresis”. Ecologists speak of “delayed functional response”. The meaning is that systems have an inertia that keeps them looking the same for awhile, even after everything, everything has changed. You can slowly raise the temperature of a glass of water until it’s 10o above boiling, and it looks like a calm liquid, not a bubble in sight. But then touch it or disturb it or drop in a grain of sand and the water explodes. (People have been scalded taking a superheated cup of coffee out of the microwave.)

And so may it be with species extinctions. The producer species have not been keeping pace with consumption for quite some time, but the consumer species goes on, apparently thriving, continuing to increase in number, though they may notice it is a little more difficult than usual to forage the evening meal. By the time the predators realize that something is awry, the game is played out and long past over. There’s no road home.

The reason can be explained in terms of exponential mathematics: a depleted prey population grows very slowly, even as the predator population is at maximum demand. Or intuition tells us the same thing: when food becomes scarce, the predators step up their hunt effort and do their best to maintain their quality of life (and their fertility) until food becomes so scarce that it is too late.  The prey species, if not extinct, is at such a low level that it will take a long time to recover, long enough for most of the predators to starve. The earth’s ocean ecologies have already been transformed beyond recognition by industrial-scale fishing methods.

In 1944, the US Coast Guard introduced 29 reindeer on the island of St Matthew off Alaska.  There had been no large mammals on the island before, and no natural predators.  It was an experiment to see if a hunting preserve could be established.  The reindeer population grew steadily at about 30% per year, first surpassing the number the island could support sustainably in about 1958.  That was about 2,000 animals.  But by 1963, inertia carried the population over 6,000.  The next winter was rather harsh, not extraordinary, but enough to devastate the over-extended population.  When wildlife wardens landed on the island the following spring, 42 reindeer remained alive [ref].

The Sixth Extinction

Between the advent of multicellular life and the current era, there have been five major extinction events, in which between 30% and 80% of all extant species vanished on a timescale shorter than can be resolved in archaeological records. These were spread over 500 million years.  We are now in the midst of the Sixth Extinction, sometimes called the Anthropocene Extinction, and it is estimated that there is already sufficient inertia in the process to insure that a substantial fraction all extant species will perish in ensuing decades, no matter what conservation efforts are undertaken, and no matter what future direction is taken by human civilization.

In 2002, world leaders represented at the Convention on Biological Diversity committed to a program targeting a significant decline in the rate of species extinction by 2010. It was assumed at the time that conservation measures at the fringe of the mainstream economy would be adequate to achieve this end. But by 2010, it was clear that this program had failed dramatically, and that the loss of biodiversity is essentially linked to the core character of human economy.

I have explained in previous blog posts my belief that ecosystems are highly co-evolved for stability. Large-scale. complex ecosystems have the property of being highly interdependent, and redundant, which creates a resistance to small disruptions. The same structure also creates a vulnerability to large disruptions. There is a “domino effect”: Once a threshold of loss is exceeded, the entire system becomes vulnerable to collapse. It is theorized that most of the species lost in the previous five extinctions succumbed to this sort of “collateral damage”.

Democracy

David Wilson has proposed that democracy is an evolutionary development of seminal import, and is what distinguishes human organization from other successful social species. Humans communicate and negotiate, and are able to arrange their cooperation in the interest of a diverse community. Contrast this to eusocial insects, for example, which enlist an army of workers in the interest of a single genome. The human analog of these systems is oligarchy and aristocracy, which Wilson sees as pulling us back toward a lower and less powerful stage of evolutionary development.

We live in a time when most of the developed world pays lip service to democracy, but in reality, deep distortions to democracy pull public policy into the service of short-term corporate profits, and a very small, very wealthy minority.

Democracy alone may not be sufficient to take us from imperial wars and an extractive relationsihp to nature all the way to world peace and environmental stewardship…but it’s a big step in the right direction. Corporatocracy is carrying us in the wrong direction,180 degrees at a rousing gallop. The people have consistently expressed more sensitivity to nature than the politicians, and there has never been a war but that the politicians have had to drag the people into it with ominous appeals to fear more than patriotism.

There’s nothing I can do, so why are you reminding me of this shit?

I return to Wordsworth. I love this poem (and am grateful to my late father-in-law for introducing me). It was written in 1806.

THE world is too much with us; late and soon,
Getting and spending, we lay waste our powers:
Little we see in Nature that is ours;
We have given our hearts away, a sordid boon!
The Sea that bares her bosom to the moon;
The winds that will be howling at all hours,
And are up-gathered now like sleeping flowers;
For this, for everything, we are out of tune;
It moves us not.–Great God! I’d rather be
A Pagan suckled in a creed outworn;
So might I, standing on this pleasant lea,
Have glimpses that would make me less forlorn;
Have sight of Proteus rising from the sea;
Or hear old Triton blow his wreathed horn.

Most of us live busy, over-scheduled lives, committed to family, friends, and more projects than we are able to complete. We feel that much depends on our efforts, and, in the last analysis, we are all alone.

We live, after all, in a hyper-individualistic culture, with a sense of who we are that is probably anomalous both across history and across nations. Many Asian cultures are subtly more collective and cooperative than ours. Hunter-gatherer cultures of our hominid ancestors (and extant hunter-gatherers today) are strikingly more communal in their organization. Much of the angst and yearning that we feel from day to day (feelings we have learned to ignore, or to blame on our own failings) may be an echo of our longing for re-connection to nature and to each other. We were never meant to go it alone.

Our individual mortality looms large, perhaps especially so for members of the life extension community.  Of course, fear of death has a biological basis and evolutionary roots. Mourning and long sadness over the loss of a loved one is ancient – gorillas and even elephants mourn their dead. But this sense that my individual consciousness is all that there is, that it depends on this body, that all is over when the light goes out, an absolute finality – this is an abysmal terror that most people historically have not lived with, and even most cultures today do not feel.

Entertain the possibility that our sense of self may be deeply distorted by culture, that there is another way to feel about our very existence. Explore opportunities for collective political action, not only as a way to save our planet, but also to reconnect to each other, to nature, and to our own souls.

pf button Human Mortality, Individual and Collective

The three-day fast: Day Four

Last week, an article about the cell biology of fasting made headlines in the science news press.  Valter Longo cites evidence that a 3-day fast can rejuvenate our immune systems, with broad anti-aging benefits.  4 or 5 days may be better yet.


 

Socially, I was a late bloomer, clinging too tightly to love, driving away partners until I was in my 20’s.  I took a full year to allow Marsha into my heart.  Four years later, she broke up with me, and it launched a full-scale spiritual crisis, beginning with three days in which I had no interest in eating.

Those of you who have probed my Aging Advice page know that I fast a day a week, water only from Wednesday evening to Friday morning.  I have grown quite comfortable with this routine.  I ease off other disciplines on Thursdays, take a day off from aerobic exercise, allow myself to sleep more and be less productive.  I still do yoga, and like to take long walks on Thursdays.

But not since I was 28 have I fasted three days.  Monday morning, I awoke with the thought that this is as good a time as any to begin a three-day fast.  If I wait longer, I will have time for fear and worry.  My mind will play tricks on me, making it harder than it has to be.


I first became acquainted with Valter Longo’s work when, in 2004, he published a remarkable paper in Journal of Cell Biology based on work he did on yeast cells for his dissertation almost a decade earlier.  The results were considered so unlikely that it had taken him that long to convince a journal editor to take a chance and publish them.  What Longo had discovered was that when he starved a colony of yeast cells, about 95% of the cells would commit suicide, using the controlled death mechanism of apoptosis.  They would disassemble their proteins, dissolve the cell membranes, and turn themselves into food for the remaining 5%.

Impossible! replied the reviewers, schooled in traditional evolutionary theory.  How could such an adaptation evolve?  The colony must be closely related genetically, and how could the 5% be genetically different from the other 95%?  And whatever that difference was, the 5% would pass on their genes, the genes of the 95% would perish, and the next generation would no longer have the suicide adaptation.  We know this from basic theory, said the reviewers.  Longo must have made a mistake in his biochemistry.  These cells are not committing suicide – they are starving to death.

“Extraordinary claims require extraordinary evidence.*”  The paper was returned to him over and over, demanding more and more validation that what he saw was really apoptosis.  It took ten years before the paper was finally accepted for publication.

Today the fact that Longo discovered is widely accepted, though the message for evolutionary theory has yet to filter through.  But Valter saw the full implication of his work:  If yeast cells had failed to read the basic textbooks in population genetics, what other animals and plants might have been similarly negligent? Yeast cells are just one example of programmed death in the biosphere.  I was honored and excited the following year when Valter invited me to join him and Vladimir Skulachev in a paper for Nature Genetics on Programmed and Altruistic Aging.


In the intervening decade, Valter has been a ubiquitous presence in the biology of aging and of caloric restriction.  Of many creative innovations he has introduced, the one he is best know for is fasting as a cancer treatment.  He has documented that a three-day fast before chemotherapy has a powerful and extraordinary effect on the metabolism: The body’s normal cells are in a heightened state of protection, and are much more resistant to chemical toxins.  Hence the discomfort, headaches and nausea that generally accompany chemotherapy are attenuated – not to mention the long-term damage.  At the same time, the cancer cells are sensitized by the fast, so that more of them are knocked out by the chemo treatment.  This is a win-win for the patient, but Valter has undertaken a long and arduous campaign to convince oncologists that such a simple protocol could be so effective.  Worst of all, no one can make a dollar from fasting.


And what of the rest of us, who don’t have cancer?  This is the subject of Valter’s most recent work, that made science news headlines last week.  He puts together evidence from mice and humans that the three-day fast is a boon for us as well.  (Here is the full text, and here is an editorial in the same issue of Cell Stem Cell putting the article in context.)

 

Evidence in this week’s Longo Article

The experiment around which the paper is written involves depriving mice of food, then looking at the stem cell environment in their bone marrow.  Fasting actually increases the number of active stem cells in the bone marrow, even as the circulating white blood count is down sharply.  Two chemical signals are identified that mediate the process:  Both IGF-1 and PKA are down-regulated with fasting.

IGF-1 (insulin-like growth factor) is an old friend, first discovered in worms in the 1990s, and later identified as a pro-aging hormone generally.  PKA (protein kinase A) is less well known, and has many independent functions, de-activating several different signals by tacking on a phosphate group.  The cell’s energy cycle uses ATP, which yields energy and is recycled in its low-energy form, AMP.  Accumulation of AMP occurs when energy stores are low, and this signals a reduction in PKA.

The article makes a point that, though the benefits of long-term caloric restriction have been studied extensively, this kind of rejuvenation of the immune system has never been observed with CR alone.

Much of the article is theoretical, connecting decline of the immune system to many of the medical issues associated with aging.  Arthritis and even Alzheimer’s disease are rooted in auto-immune reactions.  The steep rise in cancer with age is believed to be related to the immune system’s failure to detect cancer in its early stages and to eliminate pre-cancerous cells.  It is to be hoped that rejuvenating the immune system might have broad anti-aging effects.

 

Why does it work?  
Evidence for programmed aging

In write-ups of this material, the failure of stem cells with age is described as “dysregulation”, and the reason the strategy works is attributed to a clearing out of damaged and ineffective immune cells from the blood, as they are converted by the body to food.  Perhaps you have noticed that this makes little sense.  Certainly Valter knows this better than anyone, given his history, but he has chosen not to fight the abstract battle about evolutionary theory, because he knows it would likely interfere with the credibility of his other, practical and life-saving work.

The point is that if the fasting body is able to rejuvenate and multiply the bone marrow cells that are responsible for blood and immunity (hematopoietic stem cells), then it is obvious that the body could do this as well or better when it has plenty to eat.  If it wanted to.  The fact that hardship and deprivation can induce the body to rejuvenate implies that aging is a programmed choice.  Even when it looks as though the cells are suffering damage over time, that damage is entirely avoidable (indeed, repairable), and it is only with chemical switches that the repair mechanisms are turned off as we age.  In PKA and IGF-1, Longo has identified two of the signals that keep the repair mechanisms dialed down, and make our health deteriorate with age.

Why is the body intent on killing itself?  It is an adaptation for population regulation, a response to natural cycles of boom and bust in population size.  When times are good, the population expands too fast.  Aging is a way of slowing down the population boom.  This is why we age more rapidly when there’s plenty to eat.  In times of famine, there is already plenty of death, and the danger is the opposite – that the population might plunge to extinction.  This is why aging backs off in the face of hunger.  (Ideas in this paragraph are not yet standard evolutionary theory, but this is a theme that I have developed in computer simulation, and it is the core of my contribution to publications in the field.)

 

Fasting in Ancient Religious Traditions

Though they are not controlled and not founded in a knowledge of biological mechanisms, traditional writings nevertheless embody experience of large numbers of people over a long period of time, and I look to them for ideas, for cautions and confirmations.  Before writing this piece, I had the impression that fasting was recommended in many religious traditions, and I eagerly googled associations with the 3000-year-old Ayurvedic (longevity) tradition of India.  I was surprised to learn that fasting for more than a day is regarded as an extreme practice, and that Ayurvedic texts don’t provide prescriptions or recommendations for long-term fasts, but rather cautions against fasting, suggesting that fasting practice has been prevalent for a long, long time, and the ancient Ayurveda was already reacting against it.

Frequent 12-24 hour fasts, however are recommended, even prescribed in the Ayurveda.  Eating the main meal early in the day is a practice that ancient traditions and modern medicine agree on.  Avoiding food for several hours before bedtime is part of yogic practice.  For Buddhist monks in the Theravada tradition, all eating is confined to the morning hours, implying a daily fast of 16 hours.

 

Implications for the clinician, for you and me

I find it remarkable, if no longer quite surprising, that in write-ups of the therapeutic effects of fasting, medical professionals and researchers focus on what we can learn that will help us produce a drug that mimics the benefits of fasting.  Fasting is providing all the benefits with little or no downside (except temporary hunger, need for warmer clothing); but medical science is busy search for drugs that will probably target just some of the signals that fasting sends, and will probably have more serious side-effects than fasting. Longo says that the constellation of benefits from fasting “would be difficult to achieve with any pharmacological or other dietary intervention.”

It is deep in the culture of today’s medicine that the patient is passive and it is the doctor who is the agent of healing.  Medical professionals de-emphasize all that the patient can do with diet, exercise and life-style modifications to improve his own health, despite the proven power of these regimes.  Part of the problem is in the conection to capitalism, which creates a focus on what can be healed profitably, ignoring remedies that cannot be sold.

 

Fasting and weight loss

It is my experience that I don’t lose weight from fasting, presumably because I eat more before and after a fast.  Other people I know have reported similar experiences, and both ancient texts and modern medical advice agree that fasting is not an effective way to lose weight for most people.  That doesn’t mean it won’t work for you, if you have experience to the contrary.

Steve Hendricks published in Harpers an account of his own 20-day fast, embedded in a very readable account of some fasting history.  Summary here for those without a Harpers subscription.

 

Personal experience

I’m now in Day 3, and it seems long only psychologically.  In my weekly Thursday fasts, I sometimes experience headaches (one week in 5 or 6), and that hasn’t happened.  I have the luxury of no busy schedule, no deadlines.  That’s a good thing, because productivity on fast days is not reliable.  During fasts, I don’t have the focus to be able to write computer code, and writing is often slow.  But often deep and creative thoughts are given to me during fasts.

I can sit contentedly for long periods of time without feeling a need to accomplish anything, or even to get up.  I tend to a shorter night’s sleep, but enjoy naps during the day.  Once in my life I tried public speaking on a day I was fasting, and I won’t do that again.  Words come out more slowly, trying the patience of the audience.  (My one experience was speaking to the Caloric Restriction Society, and my audience understood and were patient.)

 

How long is optimal?

I wrote to Valter yesterday, asking this question.  Does he have evidence from people suggesting how long it takes for the immune reset?  Is it different for people who start with a lot of fat on their bodies compared to people who have nothing in reserve?  His answer was short and to the point:

3 days is optimal for mice. For humans 4-5 minimum, depending on what you are trying to achieve

You can already tell I have a lot of faith in Valter as a scientist, and it is easy for me to believe that, from his experience, he knows more than he is able to publish.  So I’m deep into Day 4 as I finish writing this.  I’m a little spacey and my rhythms are disrupted, but I’m not suffering or food-obsessed.  I plan to start fruit or juice soon.

pf button The three day fast: Day Four

Cholesterol, Part II

Mea culpa.  Almost three weeks ago I promised to do a little reading and report back on what to believe about cholesterol and heart disease.  It was hubris to imagine that I would be able to untangle the thicket of conflicting claims with a short course of study.  Today, my goals are far more modest, and I offer my scaled-back conclusions.  Here, I offer a tentative analysis, which I hope will prompt people more knowledgable than I to refine and correct the message.

 

The mystery

The standard medical paradigm says that eating saturated fats contributes to higher LDL cholesterol in the blood, and that higher LDL is associated with greater risk of CVD (cardiovascular disease = heart attack and stroke).  The mystery which I identified last month is that there is strong evidence both for and against this hypothesis in the mainstream medical literature.

 

Why the disparity?

Certainly one reason there is so much difficulty obtaining agreement in the field is that the majority of scientists doing research on cholesterol are funded by drug companies that have billions riding on the results.  This is not a question of “honest” science vs “corrupt” science.  It is simply unreasonable to expect that a scientist working for a statin manufacturer feels free to pursue his study objectively, and to follow the data wherever it leads.  It is hard to know the extent to which drug money has corrupted the science of cholesterol, but we can be assured that it is substantial.

Despite this major bias, I don’t think that the relationship between cholesterol and heart disease is entirely a mistake or a fraud.  Even the harshest critics of the cholesterol establishment (Fred Kummerow, Stephanie Seneff, John Abramson, Sally Fallon) admit that there is some correlation between saturated fat in the diet and cholesterol in the bloodstream.  Similarly, there is good evidence that risk of heart disease is correlated with LDL cholesterol.  A new test based on the size of the LDL particles is much more predictive – see below.)

 

Correlation and Causation

If A is correlated with B and B is correlated with C, it does not follow that A must be correlated with C.  Furthermore, even if A is correlated with C, it may be that A does not cause B, or B does not cause C, so that changing A may have no effect (or the wrong effect) on C.

To be concrete: It may be true that saturated fat in the diet is correlated with high LDL, and high LDL is correlated with high CV mortality, and still cutting saturated fat does not affect CV mortality.

Most studies linking saturated fats with LDL cholesterol have been positive [ref], and most studies linking LDL cholesterol with risk of CVD have been positive [ref].  But studies attempting to link saturated fats in the diet with a higher risk of CVD have mostly been negative [ref].  This suggests that we don’t understand the underlying mechanism behind heart disease very well, and that much of what we have done in the name of prevention may have been misdirected at intermediate targets that were not causally related to heart disease.

What is true of saturated fat reduction is even more true of statin drugs.  It is certain that statin drugs improve the cholesterol profile.  It is less clear that statin drugs save lives, and it is certainly not true that statin drugs are the best prevention strategy.

It is very convenient to have an intermediate measure (like LDL cholesterol) so that you can tell whether an intervention is working without having to wait for large numbers of people to die.  If we look for the effect of some new treatment on LDL, we can test a small number of patients and know within a few months whether it is working; but if we are looking all the way to the bottom line (how many people taking this new treatment are dying of heart disease?)  then the study must involve large numbers of subjects, followed over many years.

Almost all of what we thought we knew about saturated fats, cholesterol and CVD has been based on indirect inference.  We may have to start over, using the more costly and rigorous approach based on counting CV events in large numbers of people.

 

Blood Tests

In the 1960s, people were tested for total cholesterol in the blood, which was certainly the wrong indicator.  So bad, in fact, that total cholesterol is inversely correlated with all-cause mortality risk.  In recent decades, the standard test has been the ratio of LDL to HDL cholesterol.  These are not two different kinds of cholesterol, but rather variations in the chemistry of the droplets that transport cholesterol in the bloodstream.  Cholesterol is not water-soluble, so it is carried through the blood to all the places it is needed packaged in little droplets,  These droplets come in low-density and high-density, large and small. “LDL” is “bad cholesterol” and it refers to the low-density droplets.  “HDL” is “good cholesterol” and it refers to the high-density droplets.

Just in the last few years, there is a new blood test, which is a much better indicator of risk of heart disease and stroke than were LDL and HDL. It is a subset of the LDL droplets, the small ones, that are the basis of the new test. [Early article, 1997.  large Scandinavian study, 2014.]

(I don’t want to say the small droplets are the culprit, or the cause of heart disease. It is still unclear whether relationship between the blood test and heart disease is a causal one. In other words, if we target therapies to reduce the scoe on the small particle test.)

You may want to make sure that small particle LDL is reported the next time you get a health check-up and blood test.  It is sometimes reported as LDL III, or LDL-B.  But the larger significance of this new, more accurate test is that it should make future research studies quicker and more efficient.  Assuming that causality can be established, we will have, for the first time, a way of knowing whether a preventive therapy is working without having to wait ten years and see how many people have heart attacks.

Stay tuned…

Statins

StatinMarket Cholesterol, Part II

The scale on this chart is 100 million prescriptions in the US alone.

It is probably true that statin drugs have saved millions of lives, if the alternative is defined as inaction in the face of heart risk.  It is also true that statins are the most over-prescribed medications in the Western world, that their benefits are modest and come at a cost in side-effects that can be devastating in the long run.  There are better ways to reduce cardiovascular risk, many of which have no side-effects, or side-effects that are wholly beneficial.

The way statins work is by impeding the synthesis of cholesterol.  This is the wrong target.  We need cholesterol.  As I explained in my last post, cholesterol is what makes cell membranes in animals pliable.  Cholesterol is also an intermediate product that the body uses to make essential hormones.  Cholesterol is necessary for neurons in the brain.  If we artificially suppress the body’s production of cholesterol, we are asking for trouble.

Statins also have a powerful anti-inflammatory effect, which may be the entire reason for their effectivenesss in lowering mortaliy.  There are safer antiinflammatory agents available, including fish oil and aspirin, which seem to be the easiest route to lower cardiovascular risk.

Statin side-effects include:

  • Increased blood sugar, leading to diabetes
  • Reduced CoQ10, leading to muscle weakness and oxidative damage
  • Reduced levels of other hormones, including sex hormones that are synthesized from cholesterol
  • Muscle pains
  • Weakness
  • Low energy
  • Cognitive impairment
  • Arthritis?
  • Parkinson’s Disease?

The first item is the most troubling.  Statin drugs increase blood sugar, and increased blood sugar signals the body to age more rapidly.  In the long run, this has got to be bad for heart disease risk, and also for all other causes of mortality.  Trading heart disease for diabetes is not a good bargain.  Blood sugar (particularly fructose) also combines with cholesterol to create the chemical species that is most damaging.  Stephanie Seneff explains:

Worse than that, once LDL particles have finally delivered their contents, they become “small dense LDL particles,” remnants that would ordinarily be returned to the liver to be broken down and recycled. But the attached sugars interfere with this process as well, so the task of breaking them down is assumed instead by macrophages in the artery wall and elsewhere in the body, through a unique scavenger operation. The macrophages are especially skilled to extract cholesterol from damaged LDL particles and insert it into HDL particles. Small dense LDL particles become trapped in the artery wall so that the macrophages can salvage and recycle their contents, and this is the basic source of atherosclerosis. HDL particles are the so-called “good cholesterol,” and the amount of cholesterol in HDL particles is the lipid metric with the strongest correlation with heart disease, where less cholesterol is associated with increased risk. So the macrophages in the plaque are actually performing a very useful role in increasing the amount of HDL cholesterol and reducing the amount of small dense LDL.

Perhaps the clearest message to come out of my reading is that there are better methods of lowering CV risk than statin drugs, and that people taking statin drugs should be looking for ways to replace them with measures that have beneficial side-effects.  I divide these into two categories:

(1) those whose mechanism is like statins, and may lead to some of the same problems

  • Red yeast rice is a natural product with much the same effect profile as statin drugs, but with milder side-effects.  It may provide an alternative for people who experience muscle pain from statins , though it still interferes with CoQ10 and hormone production.
  • Niacin=Vitamin B3 is frequently prescribed in high doses by heart doctors.
  • Garlic works surprisingly well for a simple, common food, suppressing cholesterol production in the liver in a way comparable to statins.

 

(2) those that have a fundamentally different mechanism of action, and are likely to be safer

  • Hibiscus flower helps prevent the oxidation of cholesterol in the blood to its toxic form.  In tests on rabbits (more prone to heart disease than mice), hibiscus lowers the incidence of CVD.
  • Berberine (a Chinese herb) signal activation of a gene that breaks down LDL (“bad”) cholesterol
  • Resveratrol acts at a higher level, promoting the SIR-T genes that have many downstream effects: increasing pliability of hardened arteries, reducing blood clots that lead to heart attack, and also lowering LDL cholesterol
  • Tree mushrooms used in Chinese soup (Auricularia) are quite effective in lowering LDL, and I have not found information about the mechanism. [ref, ref, ref]
  • Fish oil (either from fish in the diet or from capsules) seems to reduce heart risk more consistently and more effectively than anything else, with side-effects that are almost all positive.  It works on HDL:LDL ratio by a mechanism that is not well-understood, and it is also anti-inflammatory, which lowers risk of cancer and Alzheimer’s as fringe benefits.

 

Congenital high cholesterol

There are a number of genetic defects that can cause high LDL cholesterol.  Some can be tested, but most cannot.  The defects are relatively rare (1/500) but have a substantial effect on life expectancy [ref].

There is a particular mutation on chromosome 19 that is responsible for high levels of LDL cholesterol, and experts on both sides of the divide agree that it is associated with a significant decrease in life expectancy and should be treated.  Traditional treatment is based on extra-high doses of statins.  Alternative treatments are available that are less well-documented but show indications they may be more effective than statin treatment, with fewer long-term side-effects.  I recommend this article from Life Extension Magazine.

 

Separating saturated fats from other factors in a meat-based diet

Vegetarians enjoy lower mortality rates.  How much of this is due to lower saturated fats, how much to high fiber, how much to micronutrients from fruits and vegetables?  And how much is an artifact from the association between vegetarianism and better self-care in other areas?  In this same study , vegetarians who ate fish had 10% lower mortality (over 6 years) than vegetarians who ate cheese and eggs.  Perhaps this is an indication that saturated fats are bad for you, and fish oil lowers inflammation as well as blood cholesterol.  This study suggests that the difference may be more about benefits of fish than of hazzards of eating eggs and dairy.

 Cholesterol, Part II

A diet high in vegetables is our first-line defense.

(This is the last paradox, I promise!) I began by noting that the correlation between saturated fat in the diet and cardiovascular risk is weak or non-existant [ref].  But we know that saturated fat intake is highly-correlated with animal foods in the diet, and animal products lead to higher overall mortality.  This suggests that it is something else about the plant-based diet, besides low sat-fat, that is giving the benefit.

 

Coming back to my daughter’s question

My daughter is 28 years old and a vegetarian.  Last month she asked me, “I have high blood cholesterol.  Should I be avoiding coconut oil and cocoa fat?”

From three weeks of research, my answer has to be

(E) It cannot be determined from the above information.

 

Cardiovascular risk in the context of other sound advice

Lots of exercise, weight control, low-carb diet, fish oil, daily aspirin all contribute to lowering risk of heart disase, and in the aggregate are far more powerful than statin drugs, with other health benefits as a free fringe benefit.

pf button Cholesterol, Part II

Cholesterol: A Medical Controversy – I Background

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

 

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

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

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

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

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

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

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

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

 

Differences in evaluations of statin drugs are stark

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

Deaths 65 HUS2010 Cholesterol: A Medical Controversy   I Background

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

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

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

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

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

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

———————–

Basic chemistry

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

decane Cholesterol: A Medical Controversy   I Background

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

StearicAcid Cholesterol: A Medical Controversy   I Background

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

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

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

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

oleic acid Cholesterol: A Medical Controversy   I Background

This is the “cis” form of oleic acid

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

pict12 Cholesterol: A Medical Controversy   I Background

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

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

Cholesterol

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

200px Cholesterol.svg Cholesterol: A Medical Controversy   I Background

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

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

pf button Cholesterol: A Medical Controversy   I Background