Notes from Rejuvenation Biotech Conference

San Jose Aug 21-23

Herbal Telomerase Activators

As far as I know, Product B is the best commercial telomerase activation product.  (For background read this blog entry.  All currently available telomerase activators are inadequate, and they may have only nominal effect – we don’t know.)  Product B is manufactured by Isagenix, based on cell culture testing at Sierra Sciences.  Sierra screened hundreds of herbal products, reporting their results to Isagenix in black-box mode, blind to what they were testing.

I now believe that the lowest-level ingredients in Product B (last on the list) are more potent than the highest-level ingredients (first on the list).  For the last nine months, I have been supplementing with the first four herbal ingredients in Product B: Silymarin, Ashwagandha, Horny Goat Weed and Bacopa.  I plan to look into the last six ingredients:  Boswellia, Maca, Hawthorn, Harada, Shilajit and Chia seed extract.    Complete list of ingredients here.

Note that there are no extracts of astragalus in Product B.  I have contradictory information about whether cycloastragenol is a telomerase activator.

 

CRISPR

George Church of Harvard’s Stem Cell Institute led the conference off with a summary of progress in CRISPR technology.  I had never heard of CRISPR until last year.  As of last year, it was a way to gain more control in genetic engineering.  A protein could be engineered to seek out and bind to a specific spot on a specific chromosome, so that the experimenter could now specify where in the gene would be inserted.

Well, that was so last year.  Now the protein has been replaced with an RNA sequence that can be specified as an exact complement to the particular region of DNA that is targeted.  Easier, and more reliable.  And – this is the biggest news of the conference – CRISPR can now be married to a gene promoter or repressor, so that particular genes can be turned on and off using CRISPR.  This is possible not just in cells but in living organisms, potentially in you and me.

It is my belief that aging is controlled to a great extent by gene expression.  Young gene expression creates a young body.  Our bodies know how to be young, if we instruct them to do so.  Well, we now have the language to tell the body to be young.  We also have a good selection of genes to start with, genes for hormones that we have too little or too much of as we age.  What are we waiting for.

A questioner asked George about interaction with “chromatin state”.  In any given cell, at any given time, some of the DNA is unwrapped and available for expression, called euchromatin, while the rest, called heterochromatin, is spooled around protein spindles (histones).  George indicated that the CRISPR technique works a lot better on euchromatin than on heterochromatin, as we would expect, but that it works some even on heterochromatin, and we’re learning rapidly.

CRISPR is a very new technology, still in the explosive stage of development, and I promise to write a full post about it soon.

 

Ecological consequences of longevity

Caleb Finch, who wrote the book on genetics of aging more than 20 years ago, still carries an encyclopedic knowledge of research in the field.  At RB2014, he placed aging and anti-aging in the context of human imact on the environment and environmental impact on humans.  Anti-aging leads to population growth, unless we can couple it with reduced fertility.  Population growth leads to habitat loss, species extinctions, and loss of biodiversity.  Population density also contributes to pollution, which can accelerate aging.  Particulate pollution, associated with diesel engines especially, accelerates amyloid deposits and cognitive decline.  Air pollution also exacerbates heart disease. Alzheimer’s Disease has been increasing steadily the last 40 years as heart disease has been in decline.

 

Cell Signals

I learned from Judith Campisi that senescent cells send out signals that potentiate cancer, and from Evan Snyder that stem cells send out signals that promote growth and health of cells nearby.  Yea, stem cells!  Boo, senescent cells!  Only recently, it had been thought that senescent cells were merely slackers, no longer able to perform their function, but it turns out that they emit signals that have a negative systemic effect as well.  Only recently, it had been thought that healthy stem cells were able to repair and rebuild damaged tissue, but it turns out that they emit signals that have a positive systemic effect as well.  These are global signaling properties that are just coming into focus.

 

GDF11

Brock Reeve of Harvard Stem Cell Institute gave us an update on recent work on the signal protein called GDF11 (for Growth Differentiation Factor), which circulates in the blood.  We have less GDF11 as we get older.  Just this spring, two article came out in Science which demonstrate that GDF11 can stimulate growth of new neurons and muscles.  Last year, it had been reported that GDF11 also can reverse damage to aged hearts.  It may be impractical to administer GDF11 intravenously as a systemic rejuvenating factor, but the race is on to discover promoter treatments that enhance expression of our native GDF11 gene.

Skepticism from the conference organizer

I found it ironic that Aubrey de Grey, whose SENS Foundation sponsoted the conference, expressed skepticism about this whole approach to aging.  He sees aging as a matter of accumulated damage rather than perverse signaling, and he imagines that epigenetic changes that happen with age are actually evolved for the body’s benefit.  He distinguished systematic epigenetic shifts with age, which he thinks are beneficial, from random epigenetic drift, which he thinks is detrimental.

Stem cell therapy for heart disease

Linda Marban of Capricor Inc in Los Angeles reported on research to cells from the patient himself, treat them in vitro to turn them into stem cells, grow the stem cells in a petri dish, and then inject them into the patient’s heart, where they can repair damaged tissue.  The technology was described several years ago in this Nature article.

 

Stem cells to treat Parkinson’s Disease

Stephen Minger reported on the potential for applying this same technique to teat Parkinson’s Disease.  Foetal stem cells have already been used with some success, though, of course, they tend to be rejected by the patient’s immune system.  Using induced pluripotent stem cells (IPS cells) derived fromt the patient’s own cells should solve this problem.  It is now known that the brain already contains stem cells, and that in cases of stroke and brain traum, stem cells migrate to the site of the damage and activate to repair the damage.  Minger speculates that new nerve cells might be routinely required in order to form new memories.

OVERALL, I had the impression that there are now significant anti-aging technologies poised to move out of the lab and into testing and marketing.  Funding issues, marketing, regulation and logistics will impose frustrating delays.

 

pf button Notes from Rejuvenation Biotech Conference

FDA Questions an Aspirin a Day.   I Question FDA.

For 25 years, daily aspirin for people over 50 has been standard advice from the medical profession.  A few weeks ago, the FDA changed its tune, and now recommends daily aspirin only after your first heart attack.  I’m sticking with the classic advice.  Aspirin is an anti-inflammatory with benefits that include lower risk of dementia and some cancers.  The overall reduction in death and disease adds the equivalent of about 2 years of life. Though aspirin causes stomach irritation in some people, you will know quickly if you are one of them, and can try a different NSAID.

What changed?  What were they thinking?  Although the FDA policy change has been widely publicized and there are several new consumer information pages, I have been able to get no information from them about the primary literature on which they relied.

Reading between the lines, I find hints that the decision was based narrowly on the benefit of avoiding fatal heart attacks vs the cost of stomach bleeding and ulcers.  I see no evidence they considered the benefits of aspirin in lowering cancer risk or Alzheimer’s risk.  And I suspect that in evaluating the heart benefits, they were looking only at the anti-coagulent effect (short-term) and not the anti-inflammatory effect (long-term).  (I wrote about the difference last year.)

According to Robert Temple, M.D., deputy director for clinical science at the Food and Drug Administration (FDA), one thing is certain: You should use daily aspirin therapy only after first talking to your health care professional, who can weigh the benefits and risks.
–  FDA Consumer Updates

If “one thing is certain,” it is that this advice is motivated by legal and not medical considerations.  How many of us are lucky enough to have a family doctor or GP who keeps up with the literature and drills into the statistics? If today’s doctor had time for such things, his employer would jack up his patient load.

Without seeing the basis for the decision, I can think of only two reasons they might lean in this direction.  First, there is a tendency toward “natural medicine”, or trusting the body, or erring on the side of non-intervention.  I have argued that this is appropriate in young patients, but that you can’t “trust the body” with respect to diseases of old age.  The body is not trying to optimize health; it is programmed to die; so there should be no presumption against intervention.  Second is the really cynical possibility that aspirin is not a money-maker for anyone, and damping aspirin prescriptions will increase pharmaceutical profits on statins and other expensive drugs.

Dr Mercola devoted a column to the FDA decision last week.  While I respect Dr Mercola and frequently look to him for ideas and leads, I think that in this case he has made a mistake.  He lists seven of the studies with worst outcomes, and I don’t think he characterizes them fairly.  I can only guess that Mercola has fallen for the natural anti-aging fallacy.

Study Mercola’s take-home My reading of the same article
American Heart Journal 2004 (WASH) Patients receiving aspirin treatment showed the worst cardiac outcomes, especially heart failure This study compared short-term results only for aspirin compared to more powerful anti-coagulants that are too dangerous to use long-term. All subjects had had a previous heart attack. Differences among the groups were insignificant due to small study size.
New England Journal of Medicine2005 Ten-year study at Harvard involving nearly 40,000 womenfound no fewer heart attacks or cardiovascular deaths among women receiving aspirin therapy Actually, there were 9% fewer heart attacks among women taking aspirin, but this was not statistically significant because the subjects were primarily younger women, so there were few heart attacks in either group.
British Medical Journal 2009 Aspirin therapy for diabetics produced no benefit in preventing cardiovascular events In a meta-analysis of 6 studies, aspirin produced a 10% reduction in heart attacks, but it was not significant because of sample size.
Pharmacoepidemiological Drug Safety 2009 Swedish researchers studying individuals with diabetes found no clear benefit for aspirin, but did note it can increase the risk of serious bleeding Younger diabetic patients who took aspirin had so many deaths from bleeding that it exceeded the benefits in terms of heart disease. For older diabetic patients, the lives saved from heart disease exceeded lives lost to bleeding.
Journal of the American Medical Association 2010 Scottish study found that aspirin did not help prevent heart attacks or strokes in healthy, asymptomatic individuals with a high risk of heart disease 6% reduction in deaths from all causes was not significant because of small sample size.
Journal of the American College of Cardiology 2010 Patients taking aspirin showed a higher risk for recurrent heart attack and associated heart problems My interpretation is that subjects taking aspirin had their first heart attack 4 years later than others, and as a result their second heart attack was more likely.
Expert Opinions in Pharmacotherapy 2010 British meta-analysis of 7374 diabetics concluded that aspirin does not lower heart attack risk 4% reduction in mortality and 10% reduction in heart attacks was not significant because of small sample size.

 

Results from more positive studies

There have been many studies with positive outcomes.

This meta-analysis 2002  covered 287 studies with 135,000 total patients, and overall cardiovascular risk reduction was found in the range 30%, with 17% reduction in mortality.

This meta-analysis (2003) covered 9 studies of Alzheimer’s disease, and found among subjects who had been taking NSAIDs more than 2 years, the risk was down 73%.  That is not a misprint,  Among subjects taking aspirin, the risk of Alzheimer’s was only ¼ as big.

This meta-analysis (2012) looked at cancer risk and found 25% fewer cancer cases, 15% lower cancer mortality with aspirin.

Just this week, Nicholas Bakalar, writing in the NYTimes reported on a new meta-analysis:

The analysis, published online in Annals of Oncology, found strong evidence that aspirin reduced the risk for colorectal cancer, and good evidence that it also reduced the risk for esophageal and stomach cancers. There were smaller or more variable effects for protection against breast, prostate and lung cancers.

They also found that long-term use was required. In controlled trials, there was no benefit until at least three years of use, and mortality was reduced only after five years. A “baby aspirin” of 75 to 81 milligrams was sufficient, and there was no evidence that larger doses provided added benefit.

 

Bleeding as a side-effect

A small number of patients have trouble with bleeding and upset stomach, and it is easily determined whether you are among those.  If so, stop taking aspirin.  The number of heart attacks and cancer cases prevented may also be a small number, but there is no way to know in advance, and I say, if the aspirin isn’t hurting you, take your chances.

 

History – How did we get here?

Use of willow bark to relieve pain goes back at least to the Egyptians 3,000 years ago. Native American shamans used willow for fevers and headaches.  The aspirin molecule was first isolated in the mid-19th century, and synthesized (by Bayer) before 1900.  It became the world’s largest-selling analgesic, and has been so ever since.

In the 1960s, biochemical knowledge was still rudimentary, and heart attacks were conceived as a plumbing problem.  Arteries to the heart become clogged and blood flow is impeded.  Doctors knew that the clogging was exacerbated by the tendency of blood to clot around the fatty deposits that were causing occlusion.  So it seemed that anti-coagulants (blood thinners) should lessen the risk of heart disease in the short term.  Aspirin was known to be a blood thinner, and assumed to be safe based on its long history.

Beginning in 1971, Peter Elwood and John O’Brien began the first trial of aspirin to see if it would reduce the risk of heart attacks.  Early results were positive, indicating a short-term benefit.  Early adopters were taking daily aspirin in the 1970s and as experience accumulated, statistics made a convincing case that they were having fewer heart attacks.  By the late 1980s, use of daily aspirin to lower risk of heart disease became a standard medical recommendation.

The justification for daily aspirin at the time was based entirely on statistics.  It was assumed that the benefit came from aspirin’s anti-coagulant activity.  “Inflammaging” was still in the future, but the idea that heart disease was associated with inflammation in the artery wall was just being explored.

It is only in the last fifteen years that perception of how aspirin works has shifted.  Aspirin is an anti-inflammatory agent, the prototypical non-steroid anti-inflammatory drug (NSAID).  Inflammation is associated not just with heart attacks and ischemic stroke, but also with cancer, arthritis and Alzheimer’s disease.  Daily aspirin is associated with lower incidence of all these diseases.

The long-term effects of anti-coagulants on heart attack risk proved to be complicated.  But anti-inflammatory action is the most reliable strategy we have at present for reducing risk, not just of heart disease but of all the diseases of old age.  Because of shakey ideas about blood-thinning and heart attacks, millions of people were advised to take daily aspirin.  Decades later, it was discovered that these people had lower rates of heart disease, dementia, stroke, and cancer, because of the fortuitous happenstance that aspirin is also an anti-inflammatory agent.

Incidentally, all of the five anti-inflammatory agents I listed are also blood thinners (aspirin, ibuprofen, naproxen, fish oil, curcumin).  I don’t know enough biochemistry to understand why the two should be related.

 

Is aspirin better than other anti-inflammatory supplements?

Comparison with ibuprofen and naproxen has been done, but asking only a limited set of questions.  Compared to ibuprofen, aspirin is a little more likely to irritate the digestive tract, but less likely to damage the liver.  Compared to naproxen, aspirin is not as strong, but safer.  I have not seen a comparison with fish oil or curcumin.

It should be possible to define a strength of anti-inflammatory effect, and compare different agents, but I have never seen even that done.  Of course, what we would like to see is controlled, long-term human epidemiological studies comparing effects of all five anti-inflammatory agents on four major disease outcomes (cancer, heart attacks, stroke and Alzheimer’s).  Data does not yet exist for such a study.

 

Why is there so much difference from one study to the next?

Studies of aspirin are not unusual in this regard.  This is a great unanswered question, not just in epidemiology but all through the life sciences.  Even after accounting for placebo effect and biases in perspective from one investigator to the next and differences among sample populations, there is a lot more disparity in outcomes than we can explain.  That’s life.

 

My advice

My bottom line is that most people over 50 can benefit from daily aspirin or ibuprofen, as it lowers risk of cancer, dementia, and arthritis as well as heart disease and stroke.  Diabetes patients might start a few years later. I would suggest that if you have stomach or bleeding issues with aspirin, you will know it, and stop taking it.  If you have a family history of hemorrhagic stroke, don’t mess with aspirin at all.

 

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Love, Death, and Oxytocin

Oxytocin, the “love hormone”, is one of those blood factors that we have less of as we age. A recent study connects loss of oxytocin with frailty and loss of muscle mass in old age. Could it be that oxytocin is the biochemical mediator that signals the body to live longer in response to loving connections and caring behaviors?

 

The body knows how to be young.  It had no trouble being young X years ago.  Now the body is choosing to be old, slowing down its repair and re-building functions, gradually destroying itself with inflammation, eliminating nerve and muscle cells via apoptosis.  In doing this, the body is following hormonal signals that circulate in the blood.  If the hormonal signals say, “old”, then the body is old; and if the hormonal signals say “young”, then the body will respond appropriately.

This is my premise about what aging is, how it works, and how it can be addressed medically.  (Not everyone thinks this way ─ but you already know that.)  I call it the “epigenetic theory of aging”, and I’ve blogged about it here and written more technically here.  Last summer, I listed some of the hormones that we don’t have enough of in old age, and some that we have too much of.

 

Oxytocin is a Stem Cell Signal

Oxytocin levels decline with age, and this summer, there was an article in Nature suggesting that it may be one of those signals that help to keep us young.  Aging mice with extra oxytocin retained muscle mass that was lost by mice of similar age as their oxytocin naturally declined. Oxytocin signals the muscle stem cells (aka satellite cells) to actively divide and make more muscle cells.  The study’s authors note, however, that the satellite cell receptor for oxytocin also declines with age, so that the problem of muscle loss is really compounded, and may need to be addressed at both ends.

The reduction in muscle mass in humans starts in the third decade of life and accelerates after the fifth decade, resulting in a decrease in strength and agility. Muscle ageing is characterized by a deficiency in muscle regeneration after injury and by muscle atrophy associated with altered muscle function, defined as sarcopenia. The limiting step in muscle regeneration after injury is the activation of the muscle stem cells, or satellite cells…Satellite cells from old muscle are intrinsically able to repair damaged muscle, but are reversibly inhibited by the aged niche, yet can be quickly rescued for productive tissue repair by a number of experimental methods, including heterochronic parabiosis. While the rejuvenating effects of heterochronic parabiosis have been observed in several tissues such as muscle, brain, liver, pancreas and heart the molecular mechanisms are not fully understood and…to date, few circulating molecules decreasing with age have been identified to be responsible for skeletal muscle ageing.

 

Other roles of oxytocin

Oxytocin is known for several other functions.  It suppresses our fear and protectiveness. Delivered intraveinously to women in labor (as Pitocin) it helps to strengthen contractions.  It is also thought to be related to bonding between parent and child, between lover and lover.  In popular literature, it is referred to as “the love hormone”, with some justification.  But it doesn’t necessarily make us feel good or improve our judgment; rather it shifts our feelings in the direction of more trusting, less self-protectiveness, more caring, with results that can be good or bad depending on circumstances.

Oxytocin is released in the body in response to physical touching and especially during sexual orgasm.  Massage often triggers oxytocin.

 

What is “heterochronic parabiosis”?

The research comes from the lab of Irina and Mike Conboy, who have pioneered work in “heterochronic parabiosis”.  This is an experimental setup in which an old mouse and a young mouse are joined surgically, like Siamese twins.  It has been noted that the admixture of young blood promotes wound healing and nerve growth in the older mouse.  This raises the promise of a possible path toward rejuvenation, but the experimental technique must be refined in order to answer the obvious questions

  • Can the old mouse be rejuvenated in general, systemic ways?
  • Is its life expectancy affected by addition of young blood?
  • What are the blood factors reponsible for the effect?

The Conboys are already well into the next phase,

  • designing ways to infuse blood into a mouse without the trauma of Siamese surgery, and
  • separating different hormones in the blood so they can be tested individually and in combination.

They and other researchers have concluded that it is not the red blood cells or the white blood cells, but rather the blood plasma that carries the benefit.  Blood plasma contains many dissolved hormones, sourced from all the body’s internal secretion organs.  Some are up-regulated with age, and some are down-regulated.  The hypothesis is that there is not one magic hormone that makes us young, but rather it is the quantitative balance of various hormones that signals the age state of the body.

 

You heard it first on the Aging Matters blog

I’m going to go out on a limb and suggest a theoretical hypothesis that might help to inspire and direct future research:  It is well-established that social connectivity is a predictor of longevity in humans.  But the mechanism is unknown by which social factors affect individual life span.  Perhaps oxytocin plays an intermediary role, signaling the body in response to social connection, and promoting longevity.

There is a whole branch of aging literature relating social factors to aging and mortality.  People who are more connected have lower death rates.  Sexual activity, too, has been linked to longevity, especially in men.  Married women and especially men have lower mortality rates than un-married or divorced people. People with regular volunteer activities have lower mortality rates than people who devote all their energy to pleasing themselves, after adjusting for health and mobility factors.  More money is associated with longer life, and independently, careers with more responsibility lend to longevity [British Whitehall Study].

In all these areas, it is especially difficult to disentangle cause from effect. You can’t very well randomly assign people to two groups and ask the first group to make passionate love with a standardized partner twice a week, while the second group gets equivalent exercise from walking.  Even more difficult would be to conceal from the experimental subjects (until the experiment was over) to which group they had been assigned.

In this context, understanding biochemical mediators can help to guide research and design experiments.  We should be working toward an integrated view of human health that looks upon chemistry and behavior as two lenses for viewing one underlying reality.

 

Oxytocin’s uses, present and future

Here is Dr Sahelian’s page on oxytocin.

Oxytocin has long been available as an intravenous medication used for women in labor.  More recently, there is a nasal spray that is finding intriguing applications for autism.  Experimental use of oxytocin for enhanced intimacy or sexual experience has had mixed results.  Whether it can find a role in longevity treatment is something we should know within a few years.

We look forward to the day when we can self-administer convenient doses of oxytocin and maybe enhance oxy-receptors as well.  Until then, I guess we’ll just have to make do with massages and orgasms.

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Adapt or Die => Die Sooner to Adapt Faster

In the long run, the ability of a species to evolve is more important than anything else in determining its competitive success.  This is true almost by definition: given enough time, the ability to adapt and improve will overtake any initial disadvantage.

But evolutionary theory these last 50 years has been quite skeptical of “in the long run”.  If it is driven to extinction because of a competitive disadvantage in the short run, then what matters if it has the potential to improve, eventually?

This has everything to do with aging.  A population with aging has more diversity and a faster turnover compared to a similar population in which death is only due to famine, predators, disease, etc.  So – in theory – a population with aging evolves more rapidly than a population that doesn’t age.  But “the long run” can be thousands of lifetimes, and in the meantime those individuals that die early (of aging) are at a competitive disadvantage compared to those who continue to live, and have that much more time in which to produce offspring.

Can an aging population resist invasion (by longer-lived competitors) and cohere long enough that its superior rate of adaptation turns into a decisive advantage?  This is the question that has been at the center of my research the last dozen years.  On the one hand, there is abundant evidence that aging is no accident, that it has evolved via natural selection that explicitly favors aging.  On the other hand, the theoretical argument casts doubt on the scenario where aging is selected on this basis.

The best resolution I have been able to find for this paradox is that aging has been able to evolve on this basis, and it is because the short-term advantage of unrestrained reproduction has been held in check by a different, faster-acting evolutionary principle than evolvability. Unrestrained reproduction leads to population overshoot, population crash, and extinction. This is a powerful, fast-acting evolutionary force, and populations have had to adapt by tempering individual competitiveness.  This has created an environment in which the long-term advantage of aging is relevent, and aging as a population-level adaptation can thrive on this basis.

Here is a press release for an article of mine that will appear next month in American Naturalist, demonstrating mathematically how aging might be able to evolve, despite its individual cost, based on increased evolvability at the population level.  (The cartoon is by my daughter, Maddy Ballard.)

DinoCartoon32 Adapt or Die => Die Sooner to Adapt Faster

Young Orville was given to flights of fancy, and seemed to show no interest in securing a future.

Among members of the educated public, two views of aging predominate: One is that living things wear out like machines, suffering damage that accumulates over time. The other is that aging and death are programmed into the genes to assure space in the niche for the next generation to grow up.

But both these theories were discredited more than 100 years ago. As to the first, physicists say, “That’s not the way entropy works.” Concerning the second, evolutionary biologists will tell you, “That’s not the way natural selection works.”

So among specialists in evolutionary theory, there is a third theory: Aging did not evolve directly, but rode the coattails of genes that promote fertility early in life. In this paper, two physicists challenge the evolutionists, with a model that demonstrates how “making room for the next generation” might be a viable selection mechanism after all.

Of course, the fact that the model works this way does not imply that nature works this way. But the authors argue that their model explains recent genetic data much better than the standard theory, which was formulated before the modern science of genetics.

“Many genes that cause aging have now been identified in a number of species grown in the lab,” says Josh Mitteldorf, the paper’s lead author. “Most of these genes have nothing to do with fertility,” contradicting the mainstream evolutionary theory. “Some of these aging genes have ancient roots, going back to the first protozoa, a billion years ago. Any trait that has stuck around so long must have an adaptive function.”

“Aging is a classic case of a conflict between the individual and the community,” says author André Martins. “Going back to the 1960s, the evolutionists have a belief that in such conflicts, it is always the individual interest that prevails. Our model shows otherwise.” In recent years, computer models have played a central role in the rehabilitation of “group selection”, and both the authors have previously published computer models in which aging is able to evolve because the group benefit trumps the individual cost. Read the Article

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Origin of Life: Follow-up on your comments

I always appreciate the opportunity to learn from your comments, the more so when I have ventured outside my expertise.  I was particularly excited to receive extended comments from Gary Hurd with references that were new to me and a pointer to one of my favorite biological free-thinkers, Carl Woese.  This is a brief response to Gary, with some expanded thoughts and clarifications.

I view evolution as an accelerating process.  At the same time that life has been evolving, evolution has been evolving.  That is to say, the process of evolution has become more and more efficient over time, a phenomenon I once referred to as Evolution Squared.  Recent stages of evolution have been remarkably efficient.  Multi-cellular life is only half a billion years old (at least in the form we know it, with cells specialized to form organs, appendages, circulation, nerves etc).  So the first 85% of life’s history was spent working on individual cells, their structure and metabolism.  I expect that the earliest stages of evolution were remarkably slow.

The very first self-reproducing systems had to appear by chance, and had to evolve progressively before life had really learned how to evolve.  My premise last week was surprise that the earliest cyanobacteria appeared so soon after the earth first cooled and solidified.  Cyanobacteria have a lot of cell structure and some very fancy metabolic chemistry.  This all had to be come together at a time when the evolutionary process was groping around in the dark.

I estimated that life had only 300 million years from loose alliances of molecules to cells that left a fossil record.  Gary said this number should be 500-700 million.  He’s probably right.  700 million years is the full time available from the first liquid water to the oldest fossils, and it is impossible to know whether it was late or early in that 700 million years that molecular life first self-organized.

 

Maybe LUCA was the vast blue sea

Gary pointed me to an article by Carl Woese with an alternate picture of the origin of life.

We’re accustomed to think that the Darwinian struggle for existence is a condition of life, and it has always been thus.  We imagine that cooperation arose after competition, as alliances became a potent aid in the struggle.

We get our genes from our parents, and micro-organisms get their genes from progenitor cells.  We read about bacteria that promiscuously share plasmids—“horizontal gene transfer”—and we think this is a bizarre, chimerical monstrosity.

We’re accustomed to thinking of life lived by individuals, each with its unique lineage extending back in time.  We imagine that individuals evolved first, that they diverged and competed, and later organized into predator-prey communities and more complex ecosystems.

The technology we have for inferring genetic relationship and ancient lineage is statistical analysis of the similarity of DNA sequences in widely-varying life forms today, using genes that perform the same core functions.  Presumably, these genes all derive from a common source, and the variations that they assume among present life forms tell the story of the path by which they were passed down.

Woese, who knew this evidence as well as anyone and thought about it in the broadest context, concludes that diverse branches of the tree of life cannot be traced to a single root.

The further back in evolutionary time we look, the more the notion of an “organismal lineage”—indeed, the very definition of “organism” itself—comes into question. It is time to release this notion of organismal lineages altogether and see where that leaves us.

The further we look back in time, the more horizontal gene transfer was the rule, and strict lineage the exception.  The picture that Woese invokes is of a time before separate selves, when all partook of the chemical commons, and genes were free-floating templates belonging to no one and everyone.

The universal ancestor is not a discrete entity. It is, rather, a diverse community of cells that survives and evolves as a biological unit. This communal ancestor has a physical history but not a genealogical one. Over time, this ancestor refined into a smaller number of increasingly complex cell types with the ancestors of the three primary groupings of organisms [archaea, bacteria & eukaryotes] arising as a result.

One day, an oily film walled off one little portion of the sea, and the chemicals therein spoke the word “mine” for the first time in history.

I am fascinated by this picture.  It comes from an eminent scientist, it seems plausible, and it aligns with diverse spiritual wisdom about the unity of life and with mythology of a time before our current Age of Separation.  It will be awhile before I am able to assimilate its implications.

 

Is it hard to create a self-replicating network of molecules?

I claimed last week that lab scientists had tried and failed to come up with self-replicating molecular cycles.  Gary pointed me to five reports in the literature of self-replicating chemistry.  After looking at them, I think we’re both right.  Indeed, there are examples of molecular systems that are able to copy themselves, but they work only when immersed in a soup of chemical feed that is already too complex to have arisen by chance.  Not only are the simplest molecules capable of self-replication not simple enough that they might ever have arisen in a whole pre-biotic sea of random molecules; but even these are able to assemble copies of themselves only when provided with constituents that are also too complex to be plausibly present before biology.

All present life requires three kinds of molecules: Proteins, DNA and RNA.  Proteins do the cell’s work, including the work of replicating DNA; but DNA holds the information that tells how to build a protein, so each is dependent on the other.  DNA and RNA have the essential property that they can act as templates for their own replication.  That’s the significance of the “double helix”—two strands of DNA or RNA can come unzipped, and each finds pieces to make a new mate for itself.  But in biology, this only happens with the aid of protein molecules that do the zipping and unzipping, and finding the constituents to build the copy.  To make a protein from a DNA template requires an RNA intermediary and a tiny molecular factory called a ribosome, which is itself a miracle of natural bioengineering.  This 3-component system is so complex that it could not have been the basis of the first life on earth.  So biochemists looking for a simple self-replicating system work either on proteins alone or with RNA alone.  (DNA alone is not considered viable because it is a passive informational molecule and is not capable of doing anything on its own.)

The “protein world” hypothesis has the advantage that proteins are made of amino acids, which are relatively easy to make and are plausible constituents of the pre-biotic soup.

The “RNA world” hypothesis has the advantage that RNA is both a workhorse molecule and a template for replication.  But the constituent pieces of RNA are nucleic acids which are, themselves, harder to synthesize and it is thought that the pre-biotic soup would contain only minuscule amounts of them compared to the amounts of amino acids, which were already rare (dilute) in an absolute sense.

The five papers Gary cites are interesting for what they accomplish, as well as for what they fail to accomplish:

  • Lee et al, Nature 1997   This group at Scripps Inst in La Jolla  works with a protein that is able to make more of the same protein (no RNA or DNA).  A particular protein of length 32 can act as a template to make copies of itself by joining together two pieces of length 17 and 15 residues.

A protein (or “peptide”) is a chain of amino acid molecules.  The individual pieces are called “residues” in this context.  Individual residues qualify as simple enough to have appeared by chance in the pre-biotic soup.  However, chaining them together can be done in many different ways.

For example, there are hundreds of known, simple residues.  20 of them are essential for today’s biology.  The number of different chains of length 32 that can be made using just the 20 known residues is 20 raised to the power 32=1041.

In other words, this is a hugely improbable molecule to appear spontaneously, and even so, it can’t assemble copies of itself from individual residues, but only from two halves of itself.

My judgment is that this is tremendously exciting work, it’s on the right path, but still both too complex and not effective enough to be a candidate for the first self-replicator.

  • Lincoln & Joyce, Science 2009.  This is another group at Scripps that works with RNA alone (no proteins).  The paper describes a pair of RNA molecules, each of which was effective in assembling a new copy of the other.

This is an example of a hypercycle, as I described last week—a set of molecules that are mutually auto-catalyzing.  The fully-assembed molecules are more than 100 bases in length, and they can be assembled from smaller pieces of themselves.  The smallest piece in the “feedstock” is 21 bases in length, and the largest is more than 60.

As with the protein work above, I would judge that this is tremendously exciting and promising work.  I’m grateful to Gary for pointing it out to me.  But we’re still a long way from having a candidate for the first pre-biotic chemical system.  These molecules are too large (= too complex=too improbable) to have plausibly appeared by chance in all the world’s oceans in 500 million years.  And even if one did appear by chance, it would require the other, and then the two would only be able to replicate if provided with smaller fragments.

  • Turk et al, PNAS 2010.  This group at UC Santa Cruz reports a crucial protein-building step performed by an RNA fragment that is only 5 bases long.   In order to support biology that includes both RNA and proteins, you need ribosomes, which can make a protein to order from a from an RNA blueprint.  But ribosomes are much too complex to be part of the first living things.  This paper reports that one piece of the work done by a ribosome can be accomplished by this simple 5-base RNA fragment.  5 bases linked together is a small enough molecule that it could plausibly have appeared by chance, before biology.

The Bottom Line

In summary:  I’m impressed with the progress that has been made in the search for the chemical basis of pre-biotic life, and I’m grateful to Gary for having pointed me to this literature.  We have a long way to go before we can say we understand how life got started, but we’ve made some promising steps in the right direction.

Specialists in this area of research remain divided in their fundamental pictures of the origin of life.  Some favor the protein world, some the RNA world, and some the view that I described last week, which is that life arrived on a meteor from an extra-terrestrial source.  A common criticism is that the extra-terrestrial hypothesis is vacuous, or superfluous, because it just “kicks the can down the road”.  You are still left having to explain how life got started on some other planet at some other time.  But I’d argue that the extra-terrestrial hypothesis contributes three things:

  • it helps explain why all life on earth is related, with a common chemical basis;
  • it helps explain why life arose relatively quickly after the birth of Planet Earth;
  • and it provides more time and space for the vastly improbable events that led to the first life.

The ET hypothesis makes a prediction that may someday be testable: If extraterrestrial life is discovered, or if we are visited, then the prediction is that these visitors will have metabolisms and genetics based on proteins and DNA, respectively, just like us.

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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.

 

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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.

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