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.

 

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.

StudyMercola’s take-homeMy reading of the same article
American Heart Journal 2004 (WASH)Patients receiving aspirin treatment showed the worst cardiac outcomes, especially heart failureThis 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 Medicine2005Ten-year study at Harvard involving nearly 40,000 womenfound no fewer heart attacks or cardiovascular deaths among women receiving aspirin therapyActually, 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 2009Aspirin therapy for diabetics produced no benefit in preventing cardiovascular eventsIn 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 2009Swedish researchers studying individuals with diabetes found no clear benefit for aspirin, but did note it can increase the risk of serious bleedingYounger 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 2010Scottish study found that aspirin did not help prevent heart attacks or strokes in healthy, asymptomatic individuals with a high risk of heart disease6% reduction in deaths from all causes was not significant because of small sample size.
Journal of the American College of Cardiology 2010Patients taking aspirin showed a higher risk for recurrent heart attack and associated heart problemsMy 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 2010British meta-analysis of 7374 diabetics concluded that aspirin does not lower heart attack risk4% 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.

 

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.

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.)

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

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