Growth & Aging; Creatine & Health


Promoting growth is dangerous, especially if it is done in an un-natural way.

Hormones and growth signals are tightly constrained, and highly optimized by evolution.  Too little and the body atrophies over time, failing to renew muscle and nerve tissues.  But too much and the body risks overstimulating some rogue cell, which may turn cancerous.  Navigating between these two risks is a treacherous game, and the channel of safety is narrow.  Eventually, the body falls to one side or the other, and so we must die.”*

I have read this narrative in different contexts and in countless variations.  It is the central rationale of aging according to the mainstream of Western medicine.  But we know it cannot be true.  When we are infants, every endocrine growth signal is dialed up to the max, growth hormone is through the roof, cells are dividing like crazy, and yet cancer risk is very low.  When we are old, growth hormone has dropped to nearly undetectable levels, cell division is lethargic, stem cells are few and less active–and yet the risk of cancer is at an all-time high.

Mainstream evolutionary theory says that the body is forced to make compromises, and this this is the ultimate reason for aging.  The body doesn’t want to fall apart, but its first priority is to leave as many offspring as possible in the here and now, secondarily to preserve the body to continue to create offspring later on.  Here-and-now is safer and also more effective, because of the earlier start generating grandchildren.  So the body errs on the side of short-changing the infrastructure.  

Why should the body have to compromise?  The most popular and most standard theoretical answer is that its energy is limited.  There just aren’t enough calories to do everything perfectly.  This is the Disposable Soma theory of Tom Kirkwood, a beautiful theory that fails spectacularly when confronted with the real world.  In theory, more energy should help the body avoid the need for compromise.  We should live longer the more we eat.  The truth is the opposite.  In theory, spending energy on exercise should generate damage that needs repair, while consuming energy that could have been spent to protect from old age.  Theory says that exercise should shorten life span, but the truth, again, is just the opposite.

Even if energy isn’t the limiting factor, it sounds so reasonable that the body should be forced to compromise because we so often encounter tradeoffs in different areas of our lives.  Tradeoffs involve time and money, can’t be in two places at once, can’t have children and a career, must choose between two lovers who each fulfill parts of us.  But it doesn’t always work this way.  Computers become smaller and faster and cheaper and more energy efficient with each passing year.  Filling our lives with love and fulfillment and a sense of gratitude and wellbeing also is the best single thing we can do to enhance our life expectancies.  Sometimes you can have your cake and eat it, too; compromise isn’t always required.

So the question whether enforced compromises are implicated in aging must be answered by experiment and observation–it is not a matter of theory.  

The root of the theoretical problem is the assumption that the body is doing its best to live as long as possible, and that aging and death represent failures of a system trying heroically to avoid them.  But in this case, evolutionary theory leads us astray: the body is trying to kill it self on a schedule, as it is programmed to do.

The truth is that the body knows how to be young, and it knows how to be old.  It does an exemplary job of both, each in turn.  When the body is young, it is perfectly capable of growing, healing, producing offspring and repairing molecular damage, all accomplished simultaneously and without compromise.  When it is old, it does all of these things imperfectly, if at all, as it gradually degrades and dismembers itself, using some of the same tools that were deployed for health and protection early in life: immunity, inflammation, apoptosis and cell senescence.  

This view leaves open the possibility that medical science may find the body’s epigenetic clock, may learn how to talk to the body in its own language and fool it into thinking it is forever young.

So I am motivated to leave theory behind and look to the lab experiments for the answer:  is it possible to boost growth and simultaneously to enhance longevity?



Creatine is a very simple and common molecule with nitrogen and a COOH group like an amino acid.  It occurs in all animal cells, more not plants.  1% of our blood is creatine.  Biochemistry of creatine has been studied since 1832.

Creatine promotes creation of ATP, the cell’s short-term energy storage molecule.  The way it works is this:  ATP is adenosine triphosphate, and the 3 phosphates make it a high-energy molecule.  In muscles and neurons that consume energy intensely, ATP is tapped, and one of the phosphates is degraded in the process, leaving ADP, or adenosine diphosphate.  Creatine then steps in to recharge ADP back to ATP.  It takes on a phosphate to become phosphocreatine, and then transfers the phosphate to ADP which is restored to its high-energy form, ATP.  In times of rest, the process is reversed, as ATP gives up a phosphate to creatine, and an enzyme called creatine kinase generates phosphocreatine.  Phosphocreatine can then serve as a short-term energy reservoir.

At any given time, there is something in the neighborhood of 100g creatine in our bodies.  The amount varies widely.  We make our own creatine in the kidneys and liver.  But a substantial portion of our creatine is ingested, except that those of us who eat a plant-based diet get very little creatine. “Normal reference values for creatine are lower in vegetarians [ref]”  We make less as we grow older, but it’s easy to lose the difference because of wide natural variation in creatine levels at all ages [ref].  

Creatine was first discovered to improve athletic performance in 1912.  Since stories emerged from the 1992 Olympics, creatine has been an increasingly popular supplement among body-builders.  Creatine works especially well In combination with exercise, enhancing the benefit for strength and lean muscle mass.  I found one study demonstrating these benefits in older men.  I personally have been experimenting with creatine the past 5 months, and have noticed I can do more push-ups and chin-ups, and have gained a few pounds that I flatter myself to imagine are muscle.  I have had a minor issue with cramping which might be a side-effect

But it is only since 2010 that creatine has been known as an inhibitor of myostatin (aka GDF-8).  Myostatin is a hormone that increases with age and degrades tissues, especially muscle tissues.   Inhibiting myostatin leads to more strength and muscle mass, including a stronger heart.  The action is not through more activity of muscle satellite (stem) cells, but of less wasting [ref].  

Myostatin also promotes resting levels of growth hormone while suppressing spikes of growth hormone during exercise.  This is generally thought to be a good thing, but the reasoning is indirect.  

The best effect might be the increase in muscle satellite (stem) cells, but evidence is still thin [ref], and the effect may be temporary [ref].  There is limited evidence for creatine’s benefit to cognitive performance, especially in vegetarians and the elderly [another ref].  It has been mentioned in the context of treating Parkinson’s Disease.  One study showed a decrease in the inflammation that comes after intense exercise.  


The Bottom Line

100% of people in their 60’s and beyond develop sarcopenia=loss of muscle strength.  No one likes it, and (if you need a clinical reason) sarcopenia increases risk of injury and very gradually closes the door to a world of benefits that derive from exercise.  Exercise itself is the best way to slow sarcopenia, and creatine synergizes with exercise to help in maintaining muscle mass, strength and endurance.

Strengthening the heart is likely to be a good thing, and I have a belief that endurance and motivation and exercise and longevity are all so closely linked that I’m inclined to think there are ripple benefits from creatine. Some studies show that effects fade, so I’ll  take it intermittently, one month on, a few months off.  Drink much extra water while you’re taking creatine.

Long-term effects of creatine supplementation in humans have not been studied, except for one safety study that lasted a year and found no adverse side-effects and a small 4-year study that looked at a limited number of biomarkers.

You can purchase creatine as a powder, and it is not expensive.  It is tasteless, and can be added to drinks (but not OJ), yoghurt, or smoothies.  There is no consensus on dosage.  I have seen recommendations ranging from 1 to 20 g per day.  


* Not a literal quote from anywhere, but I place this introduction in quotes just as a warning that I don’t believe it, and I don’t wish you to believe it.

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Promise of Novel Alzheimer’s Treatments

Last year, I blogged on a CDC report that Alzheimer’s Disease is more prevalent than previous epidemiology had acknowledged.  Last month at the Rejuv Biotech conference, I heard Chas Bountra tell us that

  • Alzheimer’s Disease is currently #3 among diseases of old age
  • Demographics are increasing the prevalence of AD at an inexorable rate
  • Far more than cancer and vascular diseases, AD is unknown to us–medical science really doesn’t have a clue

Boutra is in a position to direct many millions of research dollars for AD, and he says he won’t go near either of the two large branches of research on the disease.  Study of (1) beta amyloid plaques and (2) tau proteins has absorbed tens of billions of research dollars over half a century, and yet there is no agreement even about what ultimately causes AD, let alone a program for cure.  So he will only fund long-shot ideas at the fringes of Alzheimer’s research.

There is no shortage of dark horses in this field.  In recent blog posts, I described two:  Tony Wyss-Coray is beginning clinical trials using plasma transfusions from young donors, and Bioviva will soon be trying gene therapy to activate telomerase.

Further along than either of these is Dale Bredesen’s innovative approach based on the sustained application of common sense.  Bredesen reports on a trial with just 10 patients, but 9 of them showed major improvement.  This was not the kind of result that you need a cognitive test to measure; the patients came out of nursing care and went back to their jobs.  He calls the program MEND, for Metabolic Enhancement for Neurodegeneration.  

Bredesen’s starting point is a model in which AD results from a change in hormonal signaling.  There is turnover of neurons throughout our lives (this alone is a relatively new acknowledgment), and late in life, the destruction of neurons outpaces the growth of new ones.  Bredesen defines AD as the tail of the distribution, in which the destruction of neurons has become so severe as to precipitate obvious cognitive decline.  He draws an analogy to osteoporosis, which is understood as a loss of the healthy balance between the creation and destruction of bone cells (osteoblasts) that renews bone tissue and keeps bones strong.  Nerve cells in the brain do not turn over as frequently as bone cells, but the principle is the same.

Body homeostasis is maintained generally by signaling with negative feedback loops.  Biology derives its robustness from  processes that are self-limiting.  But positive feedback loops act like “switches”; they can take the body from one state to another.  Beta amyloid is at the center of a positive feedback loop; it is a mis-folded protein that tends to cause more proteins to misfold, similar in dynamics to a prion, though the feedback of beta amyloid is not so direct as in prion diseases.

In the case of beta amyloid, the protein that is misfolded is called APP, for amyloid precursor protein.  Bredesen sees APP as a switch that turns AD on, and can just as well turn AD off.  It is both a signal protein and the gunk that accumulates around neurons in the Alzheimer’s brain.

The (missing) punch line

So what is the program that Bredesen has used so successfully to reverse Alzheimer’s symptoms in ten patients?  It is multi-faceted, not easily summarized, addressing multiple risk factors through multiple modalities.  The program is also personalized, as a doctor works with each patient’s particular symptoms and particular strengths, desiging a program the patient can commit to.  This is not traditional allopathic medicine, and prescription drugs play a minor role.  Bredesen describes a program for one of the 10 patients.

(1) she eliminated all simple carbohydrates, leading to a weight loss of 20 pounds; (2) she eliminated gluten and processed food from her diet, and increased vegetables, fruits, and non-farmed fish; (3) in order to reduce stress, she began yoga, and ultimately became a yoga instructor; (4) as a second measure to reduce the stress of her job, she began to meditate for 20 minutes twice per day; [5] she took melatonin 0.5mg po qhs; (6) she increased her sleep from 4-5 hours per night to 7-8 hours per night; (7) she took methylcobalamin 1mg each day; (8) she took vitamin D3 2000IU each day; (9) she took fish oil 2000mg each day; (10) she took CoQ10 200mg each day; (11) she optimized her oral hygiene using an electric flosser and electric toothbrush; (12) following discussion with her primary care provider, she reinstated HRT (hormone replacement therapy) that had been discontinued following the World Health Inst report in 2002; (13) she fasted for a minimum of 12 hours between dinner and breakfast, and for a minimum of three hours between dinner and bedtime; (14) she exercised for a minimum of 30 minutes, 4-6 days per week. [same ref above]

(Do you ever wonder about the code language used by doctors on their prescription pads, that only pharmacists can read?  “po qhs” is prescription-ese for “by mouth at bedtime”.  Methyl cobolamin is vitamin B12.)

Bredesen’s results

The good news is that AD was dramatically reversed, especially in its early stages, with a low-cost program that does not require superhuman life style changes.  This worked in 9 cases out of 10, and the 10th case was advanced AD.  The bad news is that crafting an individualized program for the patient requires a doctor with broad knowledge both of medicine and of the patient’s history and temperament, as well as blood tests and cognitive tests.  Patience.  This is likely to be expensive and difficult to replicate in modern, assembly-line medicine where doctors are fungible cogs in a health care factory.  But then, perhaps the bad news isn’t bad–it’s pointing in the direction of the future of medicine.


This is just vibration, but at a higher frequency than human ears can hear.  Ultrasound is commonly used (at low intensity) as an imaging tool

Prof. Jürgen Götz and Gerhard Leinenga of the Clem Jones Centre for Ageing Dementia Research, Queensland, Australia have pioneered the use of ultrasound at higher intensity to break up the beta amlyloid plaques in the brain, with dramatic benefits in mice.  Mice normally don’t get AD, but they can be genetically engineered to come down with AD reliably.  It was these mice that the Queensland doctors worked with, and in most mice they were able to clear up the plaques.  There is still controversy (after 40 years) whether amyloid plaques actually cause AD or whether they are a symptom or side-effect.  So it was important to verify that the mice showed actual memory improvements, and not just better results on the diagnostic tests.  The next step is to get experience in larger animals, before the first human trials.  [Read more from Medical News Today]  [In-depth nterview with Norman Swan.  The episode also includes an interview with Saul Vileda of Stanford about planned plasma transfusion experiments in Alzheimer’s patients.]


Alzheimer’s as an Immune Disorder

A promising line of research regards AD as an immune attack on nerve cells that producers amyloid plaques as a side-effect.  It is not the neurons byt glial cells, the “in-between” cells in the brain, that trigger the immune attack.  In active brains with lots of nerve firings, the glial cells are kept in check, while inactive neurons allow the neighboring glial cells to turn themselves into immune provocateurs.

This is a link between decline of the immune system with age, increase in inflammation, and AD.  Strong circumstantial support for this perspective comes from the fact that anti-inflammatories such as NSAIDs and curcumin offer some of the best protection against Alzheimer’s risk that we currently have available.

Conversely, the healthy immune system attacks amyloid beta and breaks it up.  Biogen Corp purchased a drug based on antibodies produced by healthy humans that attacks A-beta.  Just this year, a new drug called Aducanumab, aka BIIB037, was reported to be effective in reversing cognitive decline in small, initial trials with human trials–not just mice.


DFMO and Arginine

Arginine is one of the 20 amino acids used to build proteins, and it has been found that the AD brain consumes inordinate quantities of arginine.  This begs the question whether arginine is part of the problem or part of the body’s natural solution.  Carol Colton and her Duke Univ lab are betting on the latter.  DFMO=difluoromethylornithine is a drug that blocks arginase, the enzyme that breaks down arginine.  In case that’s too many negatives for you: more DFMO means more arginine.  DFMO has already been approved as a cancer treatment, and now it has been tested in mice, and found to both decrease plaques and improve cognitive performance. [News article, Research article]

Another protein component called taurine was found last year to be beneficial for the mice genetically engineered for susceptibility to AD.  Taurine was added to their drinking water in quantities huge by human standards, equivalent to more than 2 ounces per day of pure taurine.  But improvements in cognitive performance were dramatic.  Results were reported from the Korean lab of YoungSoo Kim.   


Current “best practices”

There are currently 5 FDA-approved drugs for AD, but all of them provide symptomatic relief only, and work only for a few months.  None is able to slow progression of the disease.  [Read more from Carl Sundquist]  Last year, there was a breathless announcement by Eli Lilly about early successes with a new drug called solanezumab, but later results deflated the bubble.


What you can do to lower your long-term risk of AD

  • Regular and sufficient sleep
  • Anti-inflammatories: NSAIDs, fish oil, curcumin=turmeric
  • Weight control
  • Mental and emotional engagement
  • Yoga and meditation
  • Vigorous exercise
  • mega-doses of Vitamin D
  • Melatonin at bedtime
  • DHEA, Vit B12 and SAMe, especially for people with MTHFR genetic risk
  • Low carb diet
  • CoQ10

Fortunately, the greatest risk factors for AD are the same as for other diseases of old age, so there are broad benefits from the above program.  General risk factors are cholesterol levels in the blood, insulin resistance, and inflammation.


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Untested Treatments for Longevity, and How to Test Them

Tests with human subjects require decades, and are impossible to control, so the  gold standard for testing claims for treatments that delay aging is the controlled trial with rodents, usually mice.  Each treatment is applied to about 50 mice for their 2-3 year life span, and an equal number of controls is housed in identical circumstances.  The total cost for a single experiment can run over $200,000, and what we get for this is two full mortality curves, with and without treatment.  

You already know that aging research is the most cost-effective in medical science.  Medical costs rise steeply with age, and delaying aging by even a small amount carries enormous benefits in avoided suffering, in lives, and in medical costs. Research on life extension treatments in mice is grotesquely underfunded by any reasonable accounting of costs and benefits.  

So there is a backlog of treatments that show promise, but we just don’t know yet whether they work.  I’m going to list a dozen of my favorites and then propose a novel scheme for testing them at minimal cost.  The proposal is to run a rough screening for important increases in lifespan, using a small number of mice, and later to determine the full mortality curves for only the most promising treatments.  Further gains in cost-effectiveness can be realized by testing the treatments 2 or 3 at a time.  This leaves a lot of disentangling for the statisticians, but math is cheaper than mice.

And there is an important fringe benefit: What we really want to know is how to combine treatments to extend health span longer than is possible with any single treatment.  Almost nothing is known about how various life extension treatments interact, and it’s high time we started learning.

Here’s my suggested list

  1. Epitalon/Epithalamin
  2. MitoQ/SkQ
  3. Lapachone
  4. Spermidine
  5. Berberine
  6. Dinh lang (Policias fruticosum)
  7. Pterostilbene
  8. Gynostemma pentaphyllum (sold as “AMPK Activator” by LEF)
  9. NAC
  10. Ashwagandha
  11. Turmeric/curcumin
  12. C60


Where do these ideas come from?

The most creative science is also the highest risk, and for that reason is underfunded in today’s economic environment.  There are herbs and roots from traditional Chinese medicine and the Indian Ayurvedic tradition; there are experiments run in small, low-budget labs and experiments from Russian universities that will not be given credence until they are validated in Western labs.  The ones I am featuring today are substances that I happen to know about, and the universe of promising treatments could be greatly expanded by any expert in Oriental medicine.

A new database of life span studies has recently been announced, to be hosted at  There is an existing catalog of life span studies in animals at, which seems to be unavailable as I write this.



Decades ago, Vladimir Anisimov of the Petrov Institute in Leningrad began testing purified extracts from pituitary glands for health and longevity benefits.  In a lifetime of research, he has found many promising substances.  At the top of the list is an extract from a region of the brain known as the epithalamus.  The natural extract is known as Epithalamin.  The active ingredient is thought to be a short peptide or micro-protein with just 4 amino acids, which Anisimov named Epithalon.  In a series of experiments over the years, Anisimov finds life extension in rodents ranging from a few percent to 30%.  Treating 70-year-old humans with the extract, Anisimov reports that their mortality rate is cut in half.



This is a molecule akin to CoQ10, attached to a positive charge which causes it to be pulled into mitochondria. I have written about it previously here and here.  The molecule was developed as a research tool in the 1970s by Vladimir Skulachev and Russian colleagues, and later was recognized for potential health benefits by Michael Murphey and Robin Smith in New Zealand.  Skulachev has tested his product SkQ in mice and claims modest life extension.  A New Zealand company began selling their version, called MitoQ last year, based on experiments that show improved wound healing and neuroprotective benefits in mice.



Beta Lapachone

Tomas André introduced me to Lapachone a few weeks ago.  His French company has begun to promote the science on a web site, though they do not offer it for sale as yet.  It is a tri-cyclic molecule extracted from bark of the Pau d’arco tree in the Amazon rain forest.  In preliminary studies, it has shown potential promoting arterial health, as a cancer treatment and modifier of the energy metabolism.  Most impressive is one study in which the survival curve of mice treated with beta lapachone seems to improve over caloric restriction.



Autophagy is the name of the cell’s main clean-up process, eliminating accumulated wastes.  Spermidine promotes autophagy, and is found in many foods.  As an anti-aging agent, it has been championed by Frank Madeo of University of Graz. He reports dramatic life extension in worms and flies, and smaller life increases in life span for rodents.



Metformin is a diabetes drug that increases insulin sensitivity and dramatically lowers cancer risk. Mice fed metformin live longer.  Berberine is a naturally-occurring polycyclic molecule that reportedly has many of the same benefits.  It is extracted from the goldenseal root, which has been used in Native American and other cultures as a natural remedy and has been championed by Jonathan Wright,  In some studies, berberine improves on metformin both in its effect on glucose metabolism and in improving the lipid profile in the blood.  Like metformin, has anti-inflammatory benefits, but it is not known whether it can slash cancer risk as metformin has been shown to do.  Recently, concern has been expressed about increased risk of Alzheimer’s in patients taking metformin, and we don’t know how berberine might do on that score.  


Dinh lang (Policias fruticosum)

Dinh lang is the Vietnamese name of a traditional herbal remedy. The Parkinson’s drug sold presently as Selegiline or Eldapril or Emsam began life with the name deprenyl.  In the 1960s, it was studied by a Hungarian doctor named Joseph Knoll.  In one of Knoll’s studies, dinh lang was combined with deprenyl, with the result that each separately extended life span in mice, and two together synergized so that life extension with both was more than the sum of the two separately.  I have not seen other studies of dinh lang, and do not know where it can be purchased, or whether it has a place in traditional Chinese medicine.



Pterostilbene is a chemical cousin of resveratrol.  Both are naturally-occurring, with trace amounts in grapes, wine, blueberries and other berries.  Both are a kind of natural anti-biotic, produced by plants as a self-defense when they are threatened by fungal infection.


In 2003, Resveratrol made a splash in the press after an MIT lab discovered that it activated a class of SIR genes associated with longevity.  There were high hopes for resveratrol when it was found to lengthen life span in yeast, worms, fruit flies and fish.  Performance in mice, however, was disappointing, with life extension only for obese mice on a high fat diet.  Pterostilbene appears to have similar activity to resveratrol, but it is much better absorbed and has greater affinity for its target, so it is used in smaller quantities.  Pterostilbene deserves to be tested for life extension potential in rodents.


Gynostemma pentaphyllum

This is the powdered leaf of a traditional Oriental medicinal herb, recently popularized by Life Extension Foundation, which promotes it under the name “AMPK Activator”.  In human and rodent studies, it improves insulin sensitivity and lowers blood sugar.  In studies with fruit flies, it modestly increases life span, but it has not yet been tested for life span effect in rodents.


N-Acetyl Cysteine

Glutathione is a first-line mitochondrial antioxidant, and it is the only antioxidant for which there is any evidence of life span extension.  Unfortunately, we cannot absorb glutathione orally, and NAC has been promoted as the next best thing, as the body uses it to make glutathione. A study from Jackson Lab reports significant life span extension from NAC in male mice, but it comes with a warning about reliability of experimental protocol.  Here is a study that reports that NAC can slow the loss of brain cells in aging mice.



Withania somnifera is an Indian root herb that is used as a longevity aid in the Ayurvedic tradition, and is reported to have anti-cancer benefits.  It is a common ingredient in those herbal mixtures that promote telomerase without astragalosides (Product B, PrimalForce, Telo-100, ProxyStem)



Curcumin is an extract from the curry spice turmeric that has been used in traditional Ayurvedic medicine.  It is one of the best herbal anti-inflammatory agents, and has been found to extend life span in flies and worms.  Based on epidemiology and cell cultures, a role in preventing Alzheimer’s Disease has been proposed for curcumin.



Buckminsterfullerene is a spherical molecule made of 60 carbon atoms that was hiding in plain sight before being discovered in the 1980s.  Based on one spectacular report of life span extension in rats three years ago, it has been adopted by people willing to experiment on themselves, who share their experiences, for example, on the Longecity web site.

Pathways and Interactions

In some cases, we expect combining treatments to be a kind of duplication of effort.  It may be that the net benefit of A and B is just A.  For example, many of the treatments that are known to extend life span work through the biochemical pathway of insulin sensitivity and the glucose metabolism.  There are only a few years of human life available from this pathway, and once we add those years, no amount of tinkering with the insulin pathway will get us any more.

Conversely, if we can indeed address two pathways that are fundamentally different, then we expect positive synergies.  It may be that the net benefit of A and B together is greater than A+B.

We have a handful of interventions that reliably extend life span in mice:  besides dietary treatments such as caloric restriction, protein restriction and intermittent fasting, there is rapamycin, metformin, aspirin, maybe TA-65, some short peptides and various anti-inflammatories.  Very little is known about their interactions, and yet there are humans (some of whom read this column) who are not waiting for the data, but doing all these things at once.  


Experimenting with multiple treatments

I think it is important both to gather information about new treatments individually, and to begin collecting information about how they combine and interact when applied together.  So I have put together an experimental plan using pairs of treatments.  Since the number of pairs is much larger than the number of treatments, I propose using a small number of mice for each treatment.  For example, with 12 treatments, there are 66 pairs of treatments.  If there are just 5 mice assigned to each pair of treatments, that’s 330 mice in all–a manageable number.  This is a modest experimental effort compared to the potential for new information about 12 treatments and their interactions.  With just 5 mice for each treatment pair, the statistical power for each combination is low.  But there will be 55 mice receiving each one of the 12 treatments, so information is there, and the math can extract it.  With so few mice, we will not be able to get the clean survival curves that have become the gold standard for testing treatments in mice.  But with a technique called incremental multivariate regression, it is possible to untangle the data and determine which are the most promising treatments, and how they are likely to work in combination.

I have begun to circulate this proposal with people who are best able to implement it, and others who are best able to find funding for the project.  In coming weeks, I’ll let you know what happens.


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HGH and IGF–Promise and Danger

In the 1980s, Growth Hormone was explored by athletes to build muscles and by aging men to…build muscles.  GH made them feel younger, revived energy and sex drive and even cognitive performance.  Then the other shoe dropped:  Animals without the GH receptor lived longer, while animals with extra copies of the GH gene die early.  GH and IGF-1 are associated with higher rates of cancer, both in humans and in animals.  Now there are credible scientists seeking ways to separate the benefits of GH/IGF from the tradeoffs.  A prominent NIH research group suggests we can activate IGF-1 in some tissues and not others.  In preliminary experiments on himself, Greg Fahy has regrown thymus tissue with GH and DHEA.  Rhonda Patrick recommends saunas and weightlifting. suggests supplementing with creatine as another option.  

HGH (human growth hormone) and IGF-1 (Insulin-like Growth Factor) are closely related steroid hormones which stimulate muscle and bone growth.  GH is produced in the pituitary gland, deep in the brain, and it circulates through the blood to the liver, where it stimulates production of IGF-1.  In addition to the liver, there are local producers of IGF-1 in the body and the brain.  Most of the effects of GH are mediated through IGF-1.  Here is a good basic reference.  A few years ago, Journal of Gerontology devoted a special issue to IGF-1.

IGF-1 is part of an ancient signaling system that promotes growth and depresses life span across many species.  The system includes insulin, a protein structurally very similar to IGF-1 (hence the name).  Insulin is a mediator of life span regulation through food, exercise and the energy metabolism.  Some proteins carry instructions in the blood; they attach to receptors on the surface of a cell and tell the cell what to do.  Others get inside the cell and play a more direct role in the chemistry.  IGF-1 does both.  It has “both endocrine and autocrine functions”.

We have a lot more of both GH and IGF when we are growing children than later in life.  

This discovery in the 1970s led medical researchers and others to the hope that HGH might be a kind of youth serum, and it was explored as a treatment for weakness, low energy, and depression in the elderly.  It worked.  IGF-1 combats the loss of muscle mass in old age, both by promoting new tissue growth and retarding apoptosis (cell suicide that protects against infection and cancer, but that can kill healthy cells as we get older).  IGF-1 promotes new nerve growth in the brain, and has been linked to better cognitive performance as well as subjective feelings of youth and wellbeing.

But then it became clear that there are long-term risks associated with GH treatment, and GH treatment began to decline before it had really taken off.  In the 1950s, long before genetic engineering, the Ames Dwarf Mouse* was as a mutant strain.  It lacks the gene for GH, and it lives 50% longer than other mice of the same species.  Other mice with GH or IGF deficiencies live longer, while mice with extra copies of these same genes have shorter life spans.  [ref, ref].  But the results of lower IGF aren’t all good, and they don’t apply in all rodents [ref].  In dwarf mice, low IGF leads to insulin resistance, diabetes symptoms and cardiovascular disease when the mice are fed a high-fat diet  [ref].  IGF-1 protects heart and arteries from deterioratation with age [ref].

“Despite the compelling data for enhanced life span in the presence of GH and IGF-1 defiiency in Ames dwarf and Snell dwarf mice, a review of the literature indicates that the effects of GH/IGF-1 defiiency on life span in many other rodent models are, in many cases, inconsistent…Thus, despite the general consensus that the GH/IGF-1 pathway is a conserved mechanism of aging, the data for increased life span in response to manipulation of this pathway in rodent models remain inconsistent and appear to be the result of studies in an important subset of animal models.” [ref]

The story in people is even more complex.  Laron dwarfism is a genetic defect in the receptor for GH, which interrupts the connection GH → IGF-1.  Laron dwarfs have high GH, but low IGF-1.  (They are treatable with IGF-1.)  There is a region of Ecuador with a high frequency of Laron dwarfism [NYTimes article].

A 67-year-old man who has Laron-type dwarfism with his daughter, 5, and sons, 7 and 10.


People with Laron Dwarfism Syndrome have symptoms of premature aging, including wrinkling and obesity.  But despite high insulin, they never develop diabetes symptoms.  What about life span?  There are contradictory claims of longer and shorter life span for Ecuador’s dwarf population.

Caloric Restriction provides another signpost.  Many hormone levels are affected by CR, and the direction in which they move is a suggestion about whether that hormone can be expected to be pro-longevity or the opposite.  Luigi Fontana of Washington Univ of St Louis has been conducting a long-term study of people on chronic (voluntary) CR. He found that circulating IGF-1 levels are not different in this population.  Protein restriction is another classical life-extensio diet, and Fontana found that protein restriction quickly causes IGF-1 levels to plummet [ref].

Are higher IGF-1 levels a risk factor for cancer in humans?  Maybe–but the association is weak and statistics are subject to different interpretations [ref].


Classical Example of Antagonistic Pleiotropy?

The prevailing evolutionary theory of aging today is called “Antagonistic Pleiotropy” (AP).  The meaning is that there are genes that have multiple effects at different times in life, forcing evolution to accept costly tradeoffs (later) in exchange for peak fitness early in life.  IGF-1 is frequently cited as a prime example in support of the AP theory.  Evolution has selected IGF-1 in order to promote rapid growth, strength and development in youth, even though IGF-1 has long-term side effects that include cancer and higher all-cause mortality.  IGF-1 signaling is a pathway that is conserved over a long course of evolutionary history, helping to reconcile evolutionary theory with the existence of tightly-related genes that regulate aging across the biosphere—a relationship that took theoreticians quite by surprise when it was discovered in the 1990s.

But a closer look at the biology of IGF-1 makes support for the AP theory more dubious.  The details of where and when IGF-1 is expressed don’t fit the convenient story of AP.  There is a lot of IGF-1 early in life, but no sign of deleterious effects.  Later in life when the piper is to be paid, IGF-1 is expressed at very low levels.  It is not easy to relate high levels of IGF-1 in our teens to the cancer and heart risk in our 70’s.  

Also, experiments with “mosaic worms” have shown that the benefits of IGF-1 can be separated from the costs.  “Mosaic” means that the worms have been grown with different genetics in different tissues.  With this technique, it was shown that the pro-aging costs of IGF-1 are confined to expression in the nervous system, while the benefits come from expressing IGF-1 in muscle tissue.  Why, then, has nature not found the optimal solution, and evolved worms to express IGF-1 only in muscle tissue?


HGH to Regrow the Thymus

The thymus is a tiny gland where our white blood cells (T-cells) are trained to distinguish self from invader.  The thymus shrinks through our lifetime, and its loss has broad consequences for all the diseases of old age–autoimmunity, weaker defense against infectious disease, failure of the immune system to eliminate cancer in its earliest stages.  

Greg Fahy is an innovative biochemist and personal friend.  When he was 46, he successfully regrew his own thymus in a short, one-man experiment using HGH and DHEA.  The procedure was written up as a journal article here, and his patent on the procedure is here.  For safety, he monitored IGF-1 levels to assure that they did not exceed those in a healthy, young adult.  This year, Fahy is conducting a tiny clinical trial based on this experience.


Safe ways to enhance IGF-1?  Maybe.

Rhonda Patrick gives a succinct and powerful case for an IGF trade-off:  Better physical and mental performance vs shorter life span. She hints that you might be able to get the benefits without the costs with natural means of enhancing IGF:  physical exercise and saunas.  Physical Exercise is a safe bet, because we know there is a net benefit for longevity, as well as abundant health benefits in the here and now.  Saunas (“hyperthermic conditioning”) also boost the body’s own HGH without injecting anything.  Heat shock has a hormetic benefit for life span in rodents and especially in worms; but I know of no epidemiological evidence linking the result to either a longer or shorter life span in humans.

Creatine is a small molecule, a substance that we all have lots of in our bodies already, though less as we age.  It is a popular supplement among body-builders.  Creatine acts in some of the same anabolic pathways as GH, promoting muscle growth.  Creatine acts by inhibiting myostatin, which is a growth inhibitor, so it is the sort of double negative that makes for grammatical awkwardness.  Eating creatine triggers a burst of GH release.  Regular use of creatine boosts the background level of GH, but actually suppresses the burst of GH that comes with exercise.

In an an article from researchers at the Reynolds Oklahoma Center on Aging and National Inst of Aging, researchers suggest that it should be feasible to tease apart the benefits and costs of IGF-1 by raising IGF-1 preferentially in some tissues and not others.  DAF-2 was an early life extension gene in worms–disable it and the worm lives twice as long.  So what’s the counterpart of DAF-2 in humans?  Turns out it’s an IGF-1 receptor.  A few years later, Gary Ruvkun discovered that disabling DAF-2 in just the worm’s nervous system was sufficient to extend life span.  This suggests that it might be possible to de-couple the anabolic benefits of IGF-1 from the life-shortening consequences.  If people are like worms, that is…

*named for Ames, Iowa, not Bruce Ames

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Report from Rejuvenation Biotech Conference

Fifteen years ago, Aubrey de Grey organized the first SENS roundtable–Strategies for Engineering Negligble Senescence.  It was a small group of out-of-the-box thinkers, heretics who talked about attacking head-on the idea that aging is just part of the human condition, looking for medical (and beyond-medical) treatments that would restore strength, stamina, and alertness, and lower the risk of all the diseases of old age at once.

There followed five more SENS conferences in Cambridge, UK.  Now, SENS HQ has moved to Silicon Valley the series has been absorbed as a summer Rejuvenation Biotech conference in California.

This is the mainstreaming of anti-aging science, the product of many long years of work and relationship-building, largely by Aubrey himself.  As Joni Mitchell wisely warns, “Something’s lost and something’s gained…our dreams have lost their grandeur coming true.”  There is a lot more money, a lot more data, well-established people and funders are involved.  But there is less daring, out-of-the-box risk-taking than in the past, and my personal judgment is that we are still at a stage of understanding where high-risk science is essential.

At one point, a young man posed a question in a session devoted to cancer strategies.  The most common cancers attract the most funding, he said, and there has been little progress over the years in survival percentages in these cases.  Meanwhile, there has been dramatic progress in rare cancers, though they are the province of fringe research with little mainstream funding.  Perhaps there is an inverse correlation between funding and scientific progress.  Perhaps funding distortions favor repeat funding of long-term projects, with a resulting bias toward failed ideas.  Perhaps funding makes scientists more conservative, and impedes discovery.  This was a perspective that no one could digest, and audience and speaker moved on with embarrassed laughter.  

At the end of this page is the most exciting thing I learned at the conference, which is also the most far-flung and likely to be an artifact.


Alzheimer’s Trial using Infusion of Blood Plasma from Young Donors

Tony Wyss-Coray of Stanford has what I consider the boldest and most promising program for rejuvenation today.  He discovered last year that mice given 8 infusions of 0.1 ml blood plasma from a young mouse showed dramatic improvements in cognitive performance.  (This is the equivalent of about ½ pint of blood per infusion in human scale.)  Tony told us that there was an unpublished experiment in which similar benefits were achieved with blood from young humans infused into older mice.  The cognitive improvements last at least a few weeks, but were not tested beyond that time frame.

Take a moment to appreciate how unexpected this was.  Even for those of us who are enthusiastic about the ability of blood factors to reprogram the body’s age, we expected that many repeated treatments would be needed, and that it would be necessary to remove pro-inflammatory factors from old blood as well as adding pro-growth factors from young blood.  Most blood factors are constantly being generated and destroyed, so their lifetime in the bloodstream is only a few hours or even minutes.  It was beyond optimistic to think that so short a course of treatment would have a measurable effect.

The result was so promising that Wyss-Coray is leapfrogging over the animal testing phase.  He has formed a for-profit spinoff, proceding right to clinical trials.  (This is possible because plasma transfusion is already a mature technology, long approved for safety in other contexts.)


Thymus Regeneration

Georg Hollander presented a cogent and enlightening exegesis of the thymus, from basic function to ongoing projects.  The thymus is a small gland under the breastbone that is responsible for a crucial function of the immune system:  traing white blood cells (T-cells) to distinguish between self and other, so they can consistently attack the latter and spare the former.  In adulthood, the thymus atrophies (“thymic involution”), and in old age there is almost no thymus left, with the disastrous result that T-cells not only fail to protect our bodies from invaders, but treat our bodies as the enemy, leading to autoimmunity.  The training is performed by web-like epithelial cells, shaped like crumpled blankets, each epithelial cell in contact with up to 60 developing T-cells.  Epithelial cells must express every single protein in the genome, and there is a transcription factor called AIRE that binds to DNA, promoting “promiscuous expression.”  Curiously, AIRE works best for genes that are normally turned off by methylation or acetylation.  15% of genes are expressed only in the presence of AIRE.  There are micro-RNAs that are also necessary for promiscuous expression of all genes.  

Hollander has been working on the hypothesis that each epithelial cell succeeds in programming only a random subset of the genome, so if you have fewer epithelial cells late in life, the cells collectively will not express every single gene in the body; there will be holes in the set of all genes represented in the thymus, and as a result there will be autoimmunity.  He said we need a minimum 200-300 epithelial cells for a fully-functioning thymus that protects the body against itself.

At Wake Forest Inst, John Jackson is working on growing epithelial cells in a petri dish, then forming them on a scaffold, integrating blood vessels (vascularization) and structural (stromal) cells.  His intern Blake Johnson made remarkable progress in a single summer toward creating a functional mouse thymus.  Mice (like other small animals) have much larger thymi in relation to body size; and (like humans), they lose most of their thymic volume over their short lifetimes, with the result that their immune systems are disabled and they are vulnerable especially to cancer.

FOXN1 is a transcription factor that may be a key to thymic reactivation.  Last year, a Scottish group announced growing a fully-functional thymus and transplanting it into a mouse.  A Pittsburgh group is working on similar techniques.  Greg Fahy of 21st Century Medicine is conducting a tiny clinical trial in the coming year, using growth hormone and other blood factors to regrow the thymus in people 50-65 yo.  (Enrollment is closed; they are not seeking test subjects.)


Two paths to longevity
(Dataheads can skip this and the following section. They are just philosophy.)

Very broadly, there are two approaches to anti-aging medicine, which might be called “bioengineering” and “endocrinology”.  The question is, how much of the change that takes place with age can the body reverse with its internal resources, given the appropriate chemical signals (that’s endocrinology)?  And how much remains that must be rebuilt or replaced with prosthetics (bioengineering)?  From the beginning, SENS has emphasized the bioengineering approach–its middle name is “engineering”.  I am more optimistic about what the body might be able to do on its own, if only we can master its biochemical language.  

Significant advances have been made in bioengineering in the 15 year history of SENS.  A prosthetic limb no longer needs to be a peg leg, but can be designed to respond to neural signals.  Prosthetic eyes and ears have come down from the clouds into the realm of the feasible.  The first organs grown cell-by-cell on scaffolds in the lab have been re-implanted successfully in human patients.

But even more stunning and promising breakthroughs have appeared in the realm of chemical signaling.  In 2000, before the Bush Ban, all stem cell research depended on embryonic stem cells harvested from foetal tissue; but turning muscle or skin cells back into stem cells has turned out to be surprisingly easy (though the process is still being refined).  “Epigenetics” was an abstract noun in 2000, and it is now the fastest-growing area of biological science.  Epigenetic signaling may be the organizing principle of whole-body aging [ref, ref, ref].  Signal proteins have been identified that turn on whole systems of genes that retard aging.  Better yet, pathways that promote inflammation (e.g. TGF-β, NFkB) can be blocked, while some blood factors (e.g. FOXn1, oxytocin) turn on regenerative pathways, with the promise of rejuvenation.  Steve Horvath has pioneered a bioinformatic approach to identifying the epigenetic differences between old and young humans.


Broad strategies

Business is averse to risk.  Science is all about exploring the unknown.  It’s not exactly a match made in heaven.

Chas Bountra is deeply tied to the establishment, but radical in his own way.  He is a veteran of many years as head of research at Glaxo Smithkline, and now directs the Structural Genomics Unit at Oxford.  His focus is Alzheimer’s Disease, and tells us why:  We have a basic understanding of cancer, stroke and heart disease, and are making steady, incremental progress toward prevention and higher survival rates.  If current trends continue, dementia will be the scourge of the next generation, exacting an unaffordable social cost as patients survive for years, unable to contribute to society, to care for themselves or even to enjoy social interactions with others.

He is interested in “novel targets”.  He will not consider amyloid beta or Tau protein aggregates because, “we have spent tens of billions of dollars researching A-beta plaques and we still can’t Bountra makes an impassioned plea for open source researching.  He boasts of doing research that drug companies shun as too risky, and having succeeded in identifying more than 40 new targets that drug manufacturers have pursued and brought to the market.  His research unit publishes all data, takes no patents, and shares all ideas in academic journals.   His model: Universities take all the risk, using public monies; pharmaceutical giants make all the profits.  (Big Pharma then uses its considerable leverage in lobbying Congress to increase funding for biochemical research.)

For a commie like me, this model is tainted with corporate welfare, but while I choke on the social injustice, I admit that it is practical and effective in today’s political environment.


Oldest Aging Scientist Still Active

That title probably goes to George Martin, at 88 still deeply thoughtful and open to new ideas in his U Washington lab. I visited George a week earlier, on my way to San Francisco.  Len Hayflick, 87, works at UCSF.   At 86, Bruce Ames is still active and doing good work.  After the conference, I was privileged to visit his lab in Children’s Hospital Oakland Research Institute (CHORI).  Ames has been doing innovative biochemistry since the 1960s, and by now has persevered to see some of his heresies absorbed into the canon of public health.  After a 32-year career at UC Berkeley, he moved to emeritus status and opened his present lab in 2000.   

Bruce Ames

In 1972, Ames launched his career by investing a quick and easy lab test for mutaogenicity (and presumptive carcinogenicity) that has saved millions of dollars and countless rabbits and mice.  

In the 1980s, Ames was an early influence on my diet and helped form my understanding of aging.  In that era, we all thought about buildup of toxins and cumulative effect of carcinogens.  Ames was at the forefront, ranking carcinogens by a scheme he called HERP, which took proper account of potency and average public exposure.  The conclusion that surprised him and alienated many advocates of natural medicine was that natural carcinogens are common in the foods we eat, overwhelming the risk from pesticides and preservatives for which we were seeking tighter regulation.  Always an evolutionary thinker, Ames headed off the argument that we might be evolved to deal with natural carcinogens but not manufactured carcinogens, demonstrating that diets and lifespans of our hominid forbears made that conclusion unsupportable.

Ames was one of an elite group at the first SENS roundtable discussion in 2000, forerunner of the RB2015 conference that I attended last week.

Today, Ames argues that dozens of micronutrients are essential for both day-to-day metabolism and for long-term health.  When any of these micronutrients are in short supply, the body prioritizes the former, and the latter is shortchanged, with consequences for longevity.

In Bruce’s lab, I met Rhonda Patrick, a dynamic young post-doc who both does innovative nutritional science and has a uniquely nerdy and well-informed video blog, of health advice, broadcasting biochemistry, nutrition and metabolism for the masses.  

I can’t resist noting how pleased I was to find support in Bruce’s lab for my contrarian idea that aging is controlled in part by an evolved genetic program.


Metformin Update

I have been an advocate of metformin for everyone, and enthusiastic about Nir Barzilai’s trial of metformin as an anti-aging drug.  Last week, I learned from Brian Hanley that metformin has a dark side, to wit, a statistical association with higher frequency of Alzheimer’s disease [ref, ref].  There is a biochemical mechanism that makes the epidemiology more compelling.  B12 supplementation may mitigate the risk.

Other studies [ref, ref]  have found that diabetes patients have elevated risk of dementia, and that that risk is reduced when they take metformin.  So it’s fair to say that there is contradictory evidence, and the direction of the effect may depend on individual variation.  Here is a balanced view of both sides.

A reader of this blog, George Goldsmith has written to me that berberine is a good herbal substitute for metformin.  Everything we know about berberine looks really good–it is an anti-inflammatory as well as helping preserve insulin sensitivity, acting through the AMPK pathway.  But we have much more experience with metformin, both clinically and in the lab.  Metformin increases life span in mice, and to my knowledge, this test has yet to be performed with berberine.  Magnesium supplements also can help prevent insulin resistance, and there are other good reasons to take magnesium.  

Gynostemma pentaphyllum, sold by LEF under the brand name AMPK Activator, is another herbal alternative to metformin.



Bill Andrews was a major sponsor of the conference and a ubiquitous presence, though he did not make a presentation.  Curiously enough, the only spokesperson for telomere biology was Judith Campisi.  While Andrews has taken the position that lengthening telomeres is more than a good thing, possibly a key to reversing aging, Campisi has cautioned us that telomerase is rationed by the body, and there must be a good reason for this.  For two decades, Campisi has been the principal advocate of the thesis that telomeres are permitted to shorten in order to protect us from runaway replication of tumor cells.  

My judgment is that Andrews has it right, and Campisi is clinging to a flawed theory   At this point, overwhelming evidence tells us that short telomeres cause many more cancers than they prevent.  To her credit, Campisi has backed away from the cancer theory which she had so long propounded.   But she has yet to embrace the radical truth that telomere shortening is an evolved mechanism of programmed death (and has been since the dawn of eukaryotic life).  Campisi is a good scientist who knows as much about telomere biology as anyone on the planet; but she has afforded too much deference to the prevailing evolutionary perspective, though it is contradicted by evidence that she can (and does) recite from memory.  So her more recent papers stress the (sometimes) beneficial role of inflammatory signals in promoting wound healing, and she pursues a theory that she hopes will someday explain the devastating consequences of telomere shortening as a necessary price to pay for the signals that call forth repair and renewal.

Meanwhile, flawed evolutionary theory continues to be the principal obstruction that impedes progress toward an effective telomerase activator which, I believe, will add years to our lives.  Neither VC investors nor NIH funders have given this subject the priority it deserves.



Rejuvenation from an extract of umbilical blood
(Here is the promised most exciting, and most speculative thing I learned.)

Wuyi Kong is a researcher in regenerative medicine who spent 15 years at Stanford before returning to her native China five years ago.  She now has a private for-profit business, incorporated in Silicon Valley and relocated to China, with enough funding from the Chinese government to get tantalizing results, but not enough to do clinical trials.

She describes particles in umbilical blood that confound a basic principle of biology: that every cell comes from another cell.  She calls these medium-size particles NPRCP, for non-plasma RNA-containing particles, and has observed them in electron micrographs, as they agglomerate into stem cells.  

Time sequence shows particles aggregating into cells. This is either a Nobel Prize or an anomaly.

Time sequence shows particles aggregating into cells. This is either a Nobel Prize or an anomaly.

For 15 years, Kong has been filtering these particles from umbilical blood and injecting them intravenously, first into mice and then into humans, with spectacular results.  In her most complete and convincing paper, she damages the kidneys of mice by cutting off blood supply, then demonstrates regrowth of the kidneys after infusion with NPRCPs.  The problematic claim is that NPRCPs are non-living particles, yet they agglomerate to form stem cells, which are then ennucleated with DNA from the recipient mouse.  This is indeed strange science, but isn’t this all the more reason to replicate her experiments?    

Kong claims anecdotal evidence for erasing wrinkles and white hair turned to black.  More substantively, she says patients have improved energy and faster healing.  One semi-comatose patient with advanced AD recovered not just her consciousness but also her short-term memory.

This is the kind of speculative, creative science that I have come to expect at SENS conferences.  Most such reports do not pan out, but some of them lead to spectacularly disruptive technologies.  We can survive with no less.

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Orcas and Elephants–Aging and the Taboo Subject of Population Regulation

One species has come to sit atop the biosphere in much of the world, to dominate and transform the world’s ecosystems.  A complex of environmental crises looms, and they can’t count on evolution to change their genetics fast enough to catch their fall.  The crisis will have to be negotiated with social agreements.  Will their political organizations be up to the task of establishing a sustainable culture without a population crash of unthinkable proportions?  In all the history of life on earth, there is no precedent for this situation.

…or maybe there is…maybe it has happened before that a species has encountered the productive limits of a finite planet, and responded with widespread and peaceful cooperation to avoid ecological collapse.


My main theoretical contribution to the field of aging research has been the Demographic Theory of Aging.  It says that aging evolved in order to level the death rate in good times and hard times, so individuals don’t all die at the same time, risking extinction in periods of famine or epidemic.

The mathematics of populations is about reproduction in proportion to present numbers.  This implies either exponential growth or exponential decline.  Stable ecosystems cannot be built from populations that are growing exponentially or collapsing exponentially; and no animal species can live (for long) without a stable ecosystem. There are two common objections to this simple, straightforward logic.  

The first is that evolution doesn’t work like this.  “Evolution is about one mutation at a time, and either that mutation produces more copies of itself or less copies.”  My response is that this statement is not a law of nature but a hypothesis.  It is a picture painted not by Darwin, but by evolutionary mathematicians of the early 20th century, including R. A. Fisher and J. B. S. Haldane.  Though this particular model of evolution has been the basis of much theory for the last hundred years, the products of evolution demonstrate that group fitness frequently counts as much as individual fitness.

The second is that animal populations can be stabilized by simple feedback.  When there is plenty of grass on the plain, the rabbits increase in number; and when there is not enough grass on the plain, the rabbits starve, and their numbers diminish.  My response is that this process is too violent to produce viable ecosystems.  The problem is that deaths tend to clump together, and populations overshoot so far that they are bound to vanish to extinction.  The rabbits keep eating and reproducing as long as there is grass to eat.  After that final generation of rabbits has eaten the prairie bare, their offspring–far more numerous even than they–are born into a world devoid of grass, and they all die.  

The tool of my art is computer simulation, (and I wish R. A. Fisher had had computers to support his insight).  Computer models show consistently that ecosystems relying on starvation to regulate their populations are subject to violent swings.  In simulations, animal populations will bloom to hundreds of times the level that can be supported in the long run, only to collapse suddenly to extinction.  The same simulations show that aging is able to stabilize this dynamic.  Each individual’s death occurs on an independent schedule, so they don’t die all at once, and extinction is avoided.

In the 19th Century, the Rocky Mountain Locust was a great success in the American Midwest.  Huge clouds of ten trillion locusts covered the sky for miles in every direction.  Locusts fell from the sky and covered the ground, so thick that a man could not walk without crunching them.  Every green leaf was devoured, and the midwest became a dust bowl.  The locusts drove themselves extinct, victims of their own spectacular success.  The last locust was observed in 1902.

Population regulation is an idea that has been considered and decisevly rejected by the mainstream of the evolutionary community.  The consummate British naturalist V. C. Wynne-Edwards published (in 1962) a book about natural, evolved population regulation that was at once the denouement of his life work and the end of his career.  His theory was ridiculed and dismissed, and two generations of evolutionary scientists could not breathe the words “population regulation” or “group selection” for fear they would suffer the same fate.  But these ideas have begun to resurface in the 21st Century, and in fact it is impossible to understand natural ecologies without them.

Stabilizing population dynamics with aging…

The lion cannot chase down a gazelle in the prime of life–not fast enough.  We might imagine a time in the past when some proud, tragic lion evolved enough speed that he could easily catch any gazelle in the herd.  The genes that allowed her to do this enabled her to provide more meat for her offspring, and they flourished and crowded out the slower lions as the lion population grew.  Plentiful food assured that the population of super-lions grew and grew, until the herd of gazelles was diminished, the herd was picked clean, and the lions died all at once.  This race of lions disappeared.  Elsewhere, the lions that were just a little slower continued to live sustainably with their prey.  What we are left with is a productive and stable demographic structure.  Each gazelle matures through the prime of life, runs fast enough to escape its predators, raises a family.  Then with age, the gazelle’s speed begins to lose its edge.  The lions are able to catch the older gazelles that have already replaced themselves, but not the young ones in the prime of life.  This is a stable population dynamic, and it is made possible by aging of the prey.

…and with social behaviors

Like almost all predator birds and mammala, lions use territorial social behaviors to limit their population sizes and protect their prey.  There are a few spectacular fights to the death, but for the most part, the system is maintained through voluntary submission.  One family will hold a territory, and several non-mating individuals may lurk in the wings but not reproduce and not challenge the territory-holder, sacrificing their individual fitness entirely, waiting for an opportunity like a pool of unemployed workers waiting for a job offer.

Carl Safina: Beyond Words

This week I have been reading Carl Safina’s wonderful new book about the inner lives of animals, and the languages and social structures of three groups in particular:  elephants, wolves, and cetaceans.  He is an engaging story-teller, and after hearing one drama after another of intelligent, collective actions, I came to a new appreciation of animal societies.  Because population regulation is the center of my research, I found myself melding Carl’s ideas with my own, and thinking about conscious, communal responses to overpopulation.


Elephants and orcas have much in common.  Both orcas and elephants are apex predators, with no natural enemies.  They are also nomadic, traveling huge distances and foraging over great territories.  They use sound in ways that we might find difficult to imagine, communicating over huge distances.  Both elephants and orcas recognize hundreds, perhaps thousands of individuals, their personalities and social relations, and have names for themselves, can call to specific others over distances of many miles.  Both are guided in their migrations by elder matriarchs who accumulate decades’ of experience about feeding prospects in many and widely-dispersed locations.  Leadership in elephant tribes and orca pods is established via an elaborate political system of social relations, supported by communication modalities that a few devoted scientists, studying them for decades, have only begun to decode.

Because they live much longer than the species on which they depend, their demography must be tuned to plan ahead, or else they are in danger of devastating the species on which they depend for food.  A bloom in the orca population could wipe out salmon, so that the salmon would not recover for a long time; elephants range over many thousands of square miles, and can devastate the foilage in a region because of their prodigious demand for food.

I learned that orcas divide into two cultures.  Some orcas eat fish but not mammals; others eat mammals but not fish.  Both are highly social, and are extremely friendly, gentle, playful and careful in encouters with humans.  Fish-eating whale pods might meet other pods of fish-eating whales and greet them as old friends, talking and touching.  Likewise with mammal-eating whales.  But fish-eating and mammal-eating clans ignore one another utterly.  They overlap in territory, but they do not interact.  They don’t fight, and they don’t talk.  They swim right past one another.

Warning – the rest of this column is my own speculation, and is not established or tested science.  My theory fits the facts, but it is out on the edge.

A species may gradually evolve population regulation built into its life plan, co-evolved within an ecosystem.  This is a long, slow process.  But when a species becomes social, it may learn to hunt with suddenly far greater efficiency than when individuals were hunting separately.  Social learning is much faster than the “genetic learning” that is accomplished via natural selection.  The genes don’t have time to catch up.  So when a species of animals learns to hunt socially, it must also learn to control its population socially.  Through territoriality and other agreements–through culture and communication–the population group must maintain restraint, or it will devastate its food supply and starve to extinction.

I imagine that orcas and elephants each faced this problem many tens of thousands of years ago, perhaps hundreds of thousands of years ago.  They hunt cooperatively with devastating effectiveness.  As they learned to hunt together, they must also have learned some scheme for apportioning the privilege of reproduction, an essentially political process.  Neither species is territorial in the usual sense; they roam over huge, overlapping territories.  Via communication and enforcement systems unknown to science, they have maintained their populations at levels that allow them to feed their prodigious biomass comfortably and with little fear of starvation.

The impact of humans

All this must have changed in the 20th Century, as humans blundered into their ecologies, killing huge numbers of whales and elephants, and laying waste to their food resources.  At the same time that new political agreements, new negotiations and cultures were necessary for their survival, we have killed the oldest, largest, and wisest matriarchs who might have guided this process. 

In my fantasy, the worldwide Orca community ate only fish until they faced a crisis in the mid-20th Century precipitated by human overfishing.  They shared information and held meetings about the extent of the damage.  They were shocked and saddened by the oblivious, blundering behavior of humans, but they were too wise to try to go to war, to take retribution against humans.  Perhaps they knew that this would trigger an extermination campaign that went beyond harpoons to machine guns.  There was a deep divide in opinion; some orcas thought they had no choice but to expand their hunting to walruses, seals, and porpoises in order to continue to live with the freedom they had once known; others must have thought that hunting mammals was barbaric, akin to cannibalism.  Perhaps the two orca cultures agreed to disagree, and have lived in separate communities for decades, though their territories are not at all separate.

Can humans learn from animals?

Man is in uncharted territory because in the last 150 years we have learned to increase our life span to the point where our population growth far outstrips the growth of our historic food species.  We have made up the difference by harnessing fossil energy sources to expand our habitat, and by farming on a global scale, transforming natural ecosystems into artificial ecosystems.  We don’t know how long this process can continue, and we don’t know whether our engineering can secure the fragility of artificial ecosystems.  We have not yet begun to face the Law of Unintended Consequences.   Hence “uncharted territory”.

But perhaps we have something to learn from the orcas and the elephants.

Jon Lomberg — Intelligent Life in the Universe

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The Mystery of Aging, Solved at Last!

How many headlines have you seen that purport to reveal THE secret of aging?  Just in the last few weeks,  there have been several fundamental, earthshaking, paradigm-shifting, game-changing, disruptive discoveries–and they were very different one from another.

Why do these headlines keep popping up?  Is there truth in any of them?  …and, most interesting to me, What is it that they are all missing?

I’m a culprit in this game, too.  My publisher wants to call my forthcoming book Cracking the Aging Code.

I’m going to cover seven of these news releases below; I trust you’ll let me know if you want to hear more about any of them in particular.

What to Eat while FastingI have posted a page of recipes for my variation on Longo’s Fasting-Mimicking Diet.  These recipes are not endorsed by Dr Longo, but they have the same profile of macronutrients (calories, protein, fats, carbohydrates) as the products soon to be available from L-Nutra.

These recipes are based on fresh foods, and the fiber content is much higher than the FMD that Dr Longo has tested.  Intuition tells me that fiber can only add benefit, but this is untested.

Delay of Aging by Remote Control

“UCLA biologists have identified a gene that can slow the aging process throughout the entire body when activated remotely in key organ systems.”  [Science Daily from last fall]

AMP Kinase is a key chemical workhouse for energy production and regulation.  In this study, the AMPK gene in fruit flies was found to be a signal that controls autophagy throughout the body.  (Background: Autophagy is recycling at the cellular level.  It declines through the life span, with the result that molecular gunk accumulates and production of properly-formed proteins declines.)

Life span and health span of the flies were increased when the gene for AMPK was activated in the nervous system, and independently in the digestive system.


Role of Mitochondrial Damage vs Epigenetics

Jun-ichi Hayashi of Tsukuba University was an early enthusiast of the mitochondrial free radical theory of aging, who became convinced by his own lab results that the theory doesn’t work.

Background: Mitochondria are thousands of organelles inside a cell that burn sugar for electrochemical energy that the cell can use.  They have their own DNA and their own reproductive cycles within a cell.  They generate reactive oxygen species (ROS) as a byproduct, and it was an attractive theory to attribute aging to damage and mutations they suffer because they are at ground zero for high concentrations of ROS.

Over the last two decades, we have learned that mitochondria do indeed play a central role in aging, but the story is not about simple damage.  In his latest paper [research article, Science Daily report], researchers from Hayashi’s lab show that there is no difference in the amount of DNA damage in mitochondria from cells of young people and from old people.  Why then do mitochondria perform less well, and provide less energy in older people?  They go on to propose that it is the epigenetic programming (in the cell nucleus, not the mitochondria) that makes the difference, and they identified two genes (GCAT and SHMT2)  that may be all that is needed to restore youthful function to the mitochondria.  These genes control production of glycine, the simplest of the 20 amino acids that are common protein constitutents.  Simply feeding the cells with glycine also improved mitochondrial function.  (You can buy glycine tablets as a supplement, but the body already has a lot, so it’s a good guess you would need a lot of it to make a difference.  Food sources rich in glycine include gelatin, shrimp, spirulina, and raw ostrich meat.)


Simple Flip of a Genetic Switch

Johnathan Labbadia at Northwestern University has discovered an epigenetic switch, a set of genes that is turned on that begins the aging process in lab worms [Research article from the Morimoto lab, Science Daily summary].  Worms begin aging at the tender age of 3 days, just a few hours after adulthood, with a switch that represses Heat Shock Protein.  HSP is not jus for heat, but a high-level signal that invokes a set of responses that create resiliency in response to stress of many kinds.  In worms and in other animals, stress resistance is closely associated with longevity, and HSP is associated with longer life span in worms [ref].

Scientists who see aging as a purposeful, programmed event, myself included, look to mechanisms of epigenetic control, as we are hopeful that signaling can be modified to avert aging.  But traditional evolutionay biolgy denies that there can be such direct control of aging.  According to theory, such switches could only be flipped if flipping them increased reproduction in a way that more than offsets the loss of reproductive opportunity from aging.  In keeping with the standard theories, Labbadia and Morimoto, looked for a connection to reproduction in the epigenetic switch they discovered.  They found one, but–undermining the theory–they found that the benefits for reproduction and the costs in the form of aging could be easily separated.

“In one experiment, the researchers blocked the germline from sending the signal to turn off cellular quality control. They found the somatic tissues remained robust and stress resistant in the adult animals.”

Why doesn’t the worm do this, and get the best of both?  Must be some kind of mistake, the Northwestern team asserts.  “Dysregulation” has become a favorite word, though many have enough integrity and insight to be scratching their heads, wondering why there should be so much “dysregulation” involved in aging, when we rarely find anything else about the metabolism that is consistently dysregulated.


Older Blood Vessels are Better Protected against Oxidative Stress

This press release from University of Missouri descirbe evidence that cells of the arterial lining (epithelium) are more resistant to oxidative damage when they are older.  Research from the lab of Steven Segal used hydrogen peroxide (H2O2) as a stressor.  Peroxide is also known to be a multi-purpose signal molecule that can induce cell suicide (apotosis) in high concentrations, and can induce protective anti-aging response at lower levels [ref, ref].

The article is framed within an old and discredited view of that regards aging as a simple result of oxidative damage [ref].

Although the causes of many age-related diseases remain unknown, oxidative stress is thought to be the main culprit. Oxidative stress has been linked to cardiovascular and neurodegenerative diseases including diabetes, hypertension and age-related cancers.

It should no longer surprise us that anti-oxidants are not anti-aging [ref], or that pro-oxidants can be anti-aging [ref], or that aging is an active process controlled by central signals, not a passive process of damage [ref].


Getting to the Bottom of Aging

This article claims to find the root of aging at the cellular level.  In particular, it is in the endoplastic reticulum [background in a Kahn video]. The ER is a transport network inside the cell that directs each protein molecule to a targeted location.  It does more than this–it finishes and folds the protein after it is manufactured.  The new study finds differences between the ER of old and young cells, studied in lab worms and in cultured human cells.  [Here is a Science Daily summary.]  Proteins tend to be misformed and misfolded by the ER of old cells..

In direct contrast to the article just above on blood vessels (“oxidative stress is thought to be the main culprit” ), the claim here is that there is not enough oxidation in the ER of old cells.  It is the reduced state of the ER that is responsible for misfolding of proteins.


Diverging Paths from Parabiosis Experiments:  GDF11 and TGF-β

In the early 2000s, Irina Conboy and Amy Wagers were grad students in Tom Rando’s Stanford University lab, studying parabiosis in mice.  They learned that tissues in an old mouse could be rejuvenated by exchanging blood plasma with a young mouse.

Blood plasma is the liquid, containing dissolved signal molecules but no whole blood cells, no stem cells.  The implication was that the old tissues could receive instructions from other parts of the body (an epigenetic clock?) causing them to get older or to revert to a younger state.

Following up on this work: Now Irina and her husband Mike Conboy have a lab at UC Berkeley, where they are focusing on TGF-β as one of the signals that causes aging.  They are experimenting with a drug that blocks TGF-β receptor, and found that it has rejuvenating effects both on muscle and brain cells [press release, research article].  The implication is that excessive TGF-β in the blood is a source of aging.

Wagers is at the Harvard Stem Cell Center, where her biggest trophie so far is the discovery that GDF11 has rejuvenating effects in muscle and nerve cells.  The implication is that there is not enough GDF11 in the blood in the blood of older mammals, and this is a source of aging.

The irony is that GDF11 is a form of TGF-β.  The findings of Wagers and Conboy have diverged to the point where they have focused on the same signal as pro-aging (Conboy) and anti-aging (Wagers).

I don’t have the expertise to take sides in this disagreement, but others have noted that Wagers’s claim seems counter-intuitive. Doubts were expressed about Wagers’s findings by researchers at Novartis (a Cambridge, MA pharmaceutical lab), where David Glass claims he has been unable to duplicate Wagers’s work, and that in his experiments with mice, GDF11 seems to decline with age.

Wikipedia says, “GDF11 is a myostatin-homologous protein that acts as an inhibitor of nerve tissue growth. GDF11 has been shown to suppress neurogenesis through a pathway similar to that of myostatin.” [emphasis added].  Myostatin is an inhibitor of muscle growth whose structure is 90% homologous to GDF11.

Images of cells in the brain’s hippocampus show that the growth factor TGF-beta1 (stained red) is barely present in young tissue but ubiquitous in old tissue, where it suppresses stem cell regeneration and contributes to aging.

“The challenge ahead is to carefully retune the various signaling pathways in the stem cell environment, using a small number of chemicals, so that we end up recalibrating the environment to be youth-like,” Conboy said. “Dosage is going to be the key to rejuvenating the stem cell environment.”


Keeping your Brain Active with Balance Exercises

A pilot study by Ross and Tracy Alloway of Univ North Florida suggests that balance exercises improve working memory and protect against neurodegenerative disease. [UNF press release]  The focus of the study is termed “proprioception”, awareness of body position.

We all lose brain cells with age, and I think of Alzheimer’s dementia as one end of a spectrum.  Some herbs have been studied for neuroprotective effects.  Vigorous exercise is neuroprotective.

In parallel to my life as a scientist, I have always practiced yoga and I have taught one yoga class each week for almost 40 years.  Balance exercises are an essential aspect of yoga.  Intuition tells me there is an anti-aging benefit in yoga practice, and there is implicit evidence for this.  I think the connection between yoga and aging deserves a lot more study, but of course it cannot be done with animals, and blinded, controlled experiments are not feasible.

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