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.

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.


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.


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