Is Metformin an Anti-aging Drug?

As we age, we all lose sensitivity to insulin and begin, gradually or rapidly, to poison our bodies with excess sugar in the blood. This happens to almost everyone, and it is only when the symptom is particularly severe that it is diagnosed as (type 2) diabetes. Metformin is a drug that has been used to treat diabetes for 50 years, but it is only recently that epidemiologists have begun to notice that patients on metformin have lower rates of cancer and heart disease. Of course, cancer and heart disease were elevated to begin with in diabetics. But the question has been asked: will metformin provide a benefit for “normal” aging, and lower cancer risk for people who are not diagnosed with diabetes?

Vladimir Anisimov from University of Glasgow has proposed that it’s time to test metformin for its anti-cancer and life extension potential for non-diabetics. He is a biostatistician, an epidemiologist and not a physiologist. But a good part of the reason to think that this might work comes from theory.

Metformin and Caloric Restriction

The only intervention that is known to consistently extend life span across many different species is caloric restriction. Animals seem to be widely adapted to stabilize their populations by suppressing death from aging under conditions of starvation (and raising the internally-programmed death rate when there is plenty of food). How does the individual metabolism detect when it is starving? The signal comes mainly from the insulin metabolism. The body responds to chronically elevated insulin by decreasing sensitivity to insulin, and raising insulin levels yet further in a positive feedback loop that cascades toward death. Metformin interrupts this cycle in a manner similar to lowered food intake. Since most people don’t tolerate chronic hunger very well, a drug that offers the benefits of a lean diet without having to cut calories would be highly prized. Such a drug is called a caloric restriction mimetic, and there is some reason to believe that is what metformin does. (Many people taking metformin experience actual weight loss as well.)

The health benefits of metformin for diabetics are striking, and are not shared by other drugs that treat only the diabetes. Metformin cuts cancer rates by 37% But cancer is already elevated in diabetics. If the reduction in cancer had been to values below the rates in non-diabetics, then metformin for non-diabetics would seem to be a slam dunk. But in reality this sizable benefit brings cancer rates down just about to their level in non-diabetics, but not further.  So the benefits for non-diabetics remain speculative.

Life extension in rats and mice

Over the years, there have been many studies of metformin’s effects on mice and rats. Most show some life extension, and the best result increased life span by 38%. Metformin seems to work better for mice than rats, and better for females than males.  Here is a table (from Anisimov) summarizing results in rodents. 

StrainSexTreatmentNo. of animalsLife span, daysReferences
MeanLast 10% of survivorsMaximum
Mouse
C3H/SnFemaleControl30450 ± 23.4631 ± 11.4643[67]
Phenformin24545 ± 39.2 (+21.1%)810 ± 0 * (+28.4%)810 (+26%)
FVB/NFemaleControl34264 ± 3.5297 ± 7.3311[68]
Metformin32285 ± 5.2 (+8.0%)336 ± 2.7 (+13.1%)*340 (+16.2%)
FVB/NFemaleControl15285 ± 12396 ± 0396[69]
Metformin20304 ± 10352 ± 7359
SHRFemaleControl50388 ± 29.2727 ± 22.5814[70]
Metformin50535 ± 31.9* (+37.9%)878 ± 6.6* (+20.8%)898 (+10.3%)
NMRIFemaleControl50346 ± 11.9480 ± 9.2511[71]
Diabenol50369 ± 12.9504 ± 6.4* (+5.9%)518
129/SvMaleControl41662 ± 27.7951 ± 32.31029[72]
Metformin46573 ± 26.5 (-13.4%)*931 ± 30.41044
129/SvFemaleControl47706 ± 20.8910 ± 8.9930
Metformin48742 ± 16.3 (+5.1%)913 ± 19.2966 (+3.9%)
Rat
LIOFemaleControl41652 ± 27.3885 ± 11.3919[1,73]
Phenformin44652 ± 28.7974 ± 16.2** (+10.1%)1009 (+9.8%)
FemaleControl74687 ± 19.2925 ± 22.51054[74]
Buformin42737 ± 26.4 (+7.3%)1036± 38.9* (+12%)1112 (+5.5%)
Fischer-344MaleControl31796 ± 1701039 ± 29.61065[75]
Metformin40815 ± 1861061 ± 2.51062

The difference with control is significant: * – p < 0.05 ; ** p < 0.01 (Student’s test)
(Phenformin and buformin are chemical sisters of metformin. Metformin is prescribed for people because it has the lowest rate of complications and side effects.)

Mechanism for protection against cancer

There is also “test tube” evidence for metformin’s effect on cancer: Cancer cells are supposed to detect that they are diseased  and eliminate themselves harmlessly and promptly via a mechanism called apoptosis. Cancer can’t become cancer until this mechanism is suppressed, mutated away so that the cancer cells don’t automatically commit suicide.   In lab studies of cell cultures, cancer cells respond to metformin by restoring the apoptosis mechanism that was suppressed when they became cancerous in the first place.  Metformin shrinks tumors by inducing cancer cells to commit suicide.  On this basis, metformin is just beginning to be tried as a treatment for cancer patients, with first application to breast cancer. 

 Side-effects

Complications and risks from metformin are unusual, but they do exist. The main one is called lactic acidosis – a rare but serious disease that is almost unknown outside metformin patients. A conscientious doctor who prescribes metformin will counsel the patient to be alert to the symptoms.

Research study would be most beneficial – but who will pay the bill?

For those who are overweight in middle age or pre-diabetic, there is much to recommend metformin. But are there benefits for middle-aged people who are not in this category? The only way to know for sure is through double-blind clinical trials with at least several thousands of patients. But who will fund such a study? Metformin is a cheap, generic prescription, decades out of patent. There is no company with the motivation to invest in it.

Even if such a study is begun, it will require ten years at best before we know anything.  In the meantime, a few avid life extensionists are taking the chance and asking their doctors for a prescription, or even self-medicating through on-line pharmacies.  Perhaps we will learn from their experience.

 For basic information about healthy living for a long life,
see the author’s permanent page at AgingAdvice.org.

Anti-oxidants: A Disappointment or Worse

Oxidative damage was the prevailing theory of aging in the 1990s, and anti-oxidants became the preferred prescription for youthfulness. But in lab animals and in human studies, the cure didn’t pan out – anti-oxidants never did fulfill their potential, and this left the theorists scratching their heads. Then, in recent years the situation became curiouser and curiouser, with hints that oxidative damage might be essential for a kind of stress signal that tells the body to “stay young”.

The Theory

The theory of oxidative damage was known as the “free radical theory” of aging, and it dates to physicist Denham Harman in the 1950’s. The main evidence for it was that damaged molecules – proteins, sugars, and DNA – can be found in the cells of old people, much more so than in young people. The theory is that the cell’s energy-generating machinery (in organelles called mitochondria) is designed around forms of oxygen that are highly reactive, precisely because of their high energy content. In the process of energy generation, inevitably some of these reactive oxygen species (ROS) leak into parts of the cell where they can cause trouble by corroding essential molecules.

From the first, some noted that there were some problems with the theory: One was the pace. You might imagine that these damaged molecules would accumulate gradually over a lifetime, but in fact they are found only in modest quantities until cells become very old, when the damage appears suddenly to be quite severe. And there was a paradox: Muscular activity was known to use energy at a rapid rate, and spurts of exercise generate free radicals far faster than the body can “clean them up”. Yet people (and animals) who exercise live longer, on average than those who don’t. And activity is much higher in youth, when damage seems to be accumulating slowly, than they are in old age, when the damage becomes a catastrophe.

Nobody (except maybe Cynthia Kenyon) stopped to ask: Why should we expect a Mayfly to accumulate as much oxidative damage in one day as a Galapagos tortoise does in 100 years?

 

The Remedy

If aging was caused by oxidative damage, then medicines that protect against oxidative damage might be able to retard aging. In the 1990s, the race was on to test anti-oxidants for their life extension potential. The body’s own anti-oxidant system sits on a foundation of three substances: glutathione (GSH), superoxide dismutase (SOD), and ubiquinone (also called Coenzyme Q, sold as a supplement called CoQ10). All of them are problematic for oral dosage. Glutathione is produced in the body as-needed, and only lasts a few minutes. There is a supplement, n-acetyl cysteine or NAC, which is a precursor to glutatione, but, once again, no one has been able to demonstrate life extension with NAC supplemention of lab animals. SOD is even more transient, but there is a cantaloupe extract called glisodin that purports to stimulate the body’s production. No life extension has been demonstrated with glisodin supplementation.

The least difficult is CoQ; still, absorption through the stomach is poor, and very little of it gets through to the mitochondria where it is needed*. There is some evidence that CoQ10 lowers risk of heart disease, especially for people taking statin drugs, which knock out the body’s own CoQ10. In lab animals, too, supplementing with CoQ may improve health, but it has failed to extend life span.

Lab scientists like to study aging in roundworms, C. elegans, because they are easy to grow in a petri dish and they have a fixed, short life span. In the 1980s, one of the first discoveries about aging in worms was that many genes affect life span. The capacity to disable individual genes or to snip them entirely out from the chromosome was developed in the 1980s. It was discovered that removing a particular gene made the animals longer than normal worms that had the gene. The gene was dubbed CLK-1, suggesting that it might be a “clock” for aging. Remove one copy of the gene, and the worms live twice as long. Remove both copies and the worm lives 10 times as long!  What does this gene do, such that removing it has such life extension power? It turned out that CLK-1 was an essential step toward making the worm’s version of CoQ!

This was completely unexpected. Disable the worm’s chief mitochondrial anti-oxidant, and the worm lives ten times longer! But the knock-out blow for anti-oxidant supplements came in 1994, with the Finnish “ATBC study”.  It turns out that vitamins A, C and E are also anti-oxidants. 30 thousand Finnish smokers were enrolled in a trial large enough to see even modest improvements in cancer rates and overall mortality. The study did discern a difference – in the wrong direction. People receiving the supplements were slightly more at risk for cancer, and significanctly more likely to die.

 

Why did anti-oxidant therapy fail to extend life span?

The counter-productive role for anti-oxidants was so unexpected that it was at first dismissed as certainly a statistical fluke. But other studies since ATBC have confirmed the same thing: for extending life span, anti-oxidant vitamins are worse than useless.

Then, ten years later, another line of research offered a possible hint about the meaning of these results – the physiology behind the epidemiology.

Loss of insulin sensitivity is a classic hallmark of aging. As we get older, we poison ourselves with sugar, as I wrote a few weeks ago. Exercise has been known to help preserve insulin sensitivity, but here’s what was found in some lab studies in the mid-2000s: anti-oxidants can block this benefit.

This suggests a hypothesis that is on the edge of geriatric medicine: Free radicals play a vital role in the signaling that controls the rate of aging. It is precisely the chemical damage that is done by vigorous exertion that tells the body to try harder, to dial up the defenses that can slow the aging process.

When the body is stressed, it rises to protect itself. The surprising thing is that frequently the body is able to overcompensate for the stress-induced damage. The body lives longer stressed than un-stressed. This effect is called hormesis, and it has been seen with exercise, with starvation, with many toxins and even with low doses of ionizing radiation.

You may be wondering: if the body is capable of dialing up its defenses even when stressed, why would it not do so all the time? Aren’t we programmed by natural selection to be as strong and as healthy as we are able to be? Isn’t it part of that program to resist the disintegration of old age with whatever resources the body can muster?

This reasoning is right on the money, and it has a profound implication. The body is not doing its best to avoid aging. The body – “willfully” in some genetic sense of the word – allows damage to accumulate. Protective mechanisms are turned off in old age, and aging is permitted to overtake us.

I have promoted a theory that this is done to help stabilize population levels by leveling the death rate. In times of plenty, when stress is minimal, aging provides a measure of population control. But when times are stressful, there are plenty of individuals dying of famine or hardship, and aging steps aside. “Life is tough enough now – slow down the suicide train!”

 

Oxidation and inflammation

There’s no doubt that oxidative damage to the body’s chemistry accompanies aging, and it accelerates at older ages. But this damage is not inevitable. I suspect that the high rates of damage in old age come not from the body’s everyday energy metabolism, but from chronic inflammation, which is known to rise catastrophically with advanced age. Inflammation is the body’s own front-line defense against microbes, turned against the self in old age as a mechanism of programmed death. Oxidative damage may be self-inflicted.

 

Bottom line advice for preserving your health

Skip the anti-oxidants. Bring on the anti-inflammatories. I recommend omega-3 oils, turmeric, ginger, and daily aspirin or ibuprofen.

*A renowned Russian biochemist, Vladimir Skulachev invented a form of CoQ with an extra tail on the end of the molecule that is designed to be sucked up by mitochondria. It is known affectionately as SkQ, and it shows promise for life extension in mice, and has been used as eye drops for treatment of macular degeneration and presbyopia.

Mortality and Life Expectancy

I read a few weeks ago about a study where vitamin D supplementation reduced all-cause mortality rates by 6%. How many years would that add to life expectancy? I wondered.

6% of a 75-year life span would mean 4½ extra years, I thought, naïvely.

I pulled up a mortality table (from the Social Security Admin)  and did the calculation in a spreadsheet. The two lines were barely distinguishable. A 6% drop in mortality only increases life expectancy by 7 months.

 

What’s going on?

This plot is telling us something deep about the way in which biological aging works. The death rate climbs rapidly with age, and effectively imposes an upper limit on life span that is difficult to circumvent.

If the death rate did not increase with age, then it would be true that subtracting 6% from mortality would add about 6% to life expectancy. That’s where the intuition came from about 4½ years. But with a death rate that increases with age, you “have to work a lot harder” to get an improvement in life expectancy. And in reality, the mortality curve doesn’t just rise with age – it rises at an accelerating rate.

For late life, the mortality curve becomes a wall of death.

The general relationship between mortality and life expectancy

Once I had set up the spreadsheet, it’s easy enough to ask the general question: How much does life expectancy improve for a given change in mortality? The answer I found was: very slowly

To add just 5 years to life expectancy, we would need to slash the mortality rate by more than 40%. This is a counter-intuitive statistic – and a discouraging one. By optimistic accounts, taking a daily aspirin or ibuprofen lowers mortality by 13%.  But even this major drop translates to only 2 years. From another perspective, 2 years is a windfall. Aspirin costs practically nothing and imposes minimal risk and less inconvenience.

The optimistic way to see this relationship

There is another perspective on the “wall of death”, about which advocates of life extension have written compellingly. In medical research, we are working piecemeal to chip away at the mortality rate from one disease and another. But if the fundamental rate of aging can be slowed, this will push the curve not down but to the right. This will have as much benefit as many decades of progress in cancer and heart disease.

Caloric restriction offers a bit of this. CR mimetics, therapies that focus on gene expression and signaling may offer a health dividend comparable to the collective product of all of 20th century medical science.

Telomerase as a Fountain of Youth

I’ve been to three conferences and one company visit, all in the last two weeks. Telomerase has been a common theme.

When cells divide, their chromosomes lose a bit of their tails (telomeres) at each end. Though no information is lost, this is a process that can’t go on forever. Indeed, cells are programmed to die when their telomeres get too short. And here’s something that is less well appreciated until recently: before they die, the cells in our body with short telomeres can do a lot of damage. They send out chemical signals that can cause inflammation leading to cancer, heart disease, and dementia.

As we get older, the cells have been through more generations, and the telomeres get shorter. The body knows how to make them long again: there is an enzyme, telomerase, for this express purpose. But the body keeps telomerase locked in a strongbox*, and geneticists haven’t yet figured out how to reproduce the key.

Short telomeres are associated with a steep rise in mortality, independent of age. It may be that telomere length is one of the body’s clocks by which it tells how old it is. It may be that simply lengthening telomeres can set the body’s clock back.

You’d want to try this with mice first, but the trouble is that it’s a difficult study because mice don’t keep their telomerase locked up. Their telomeres are always plenty long. So in order to do the study, you have to first create an artificial strongbox in the genome, then lock the telomerase up to see the animals age, then unlock it to see if the animals get young again. This study was done at Harvard Med School in 2010, and the results were amazing and spectacular. The mice degenerated terribly without telomerase, then they regrew their atrophied tissue when telomerase was turned on. They got smarter and stronger and their hair grew back. It was all we could have hoped.

But perhaps it was a special case, since the mice had been artificially deprived of telomerase to begin with. Still, the experiment shows great promise.

Cut to the chase: What can we do right now to get telomerase into our bodies?

You can’t eat telomerase or even inject it, because it is only effective inside the cell nucleus. But every cell knows how to make telomerase. The trick is to signal the cell to make its own.

Strategies with supplements and medication have just become available the last few years. Several products now on the market are effective, though none is nearly strong enough to actually halt (or reverse) telomere loss. Claims are often couched in FDA-sanctioned language, and published results are scarce. But I have judged that the potential for better health and longer life is too great to wait until the dust clears before beginning to treat myself.

Several extracts of the Chinese herb astragalus (huang qi, 黄芪) have been found to stimulate expression of telomerase. Silymarin from milk thistle is another publicly known ingredient. Some products have ingredients claimed as trade secret.

  • Astragaloside IV and Cycloastragenol are available from Chinese suppliers Astraglaxo and Crackaging. They are still rather expensive, because only trace amounts of each compound are found in astragalus root – but costs are dropping rapidly. Theoretically, whole astragalus should contain too little of these compounds to be of any use, though there is one study that claims whole astragalus is effective in activating telomerase.

Cycloastragenol is claimed to be much more effective than Astragalocide IV, but the compounds are closely related and knowledgable chemists with whom I’ve spoken claim that Astragalocide IV turns to cycloastragenol in your stomach.

The most expensive and best tested of the astragalus formulations is TA-65, a secret, patented formula. How can it be both secret and patented? The patent covers several different chemical compounds. A lab analysis, published online, claims that TA-65=cycloastraganol.

  • TA-65 (from TA-Sciences) is the best-documented and most expensive of the products listed here. A few weeks ago, I reported that TA-65 was the same as cycloastragenol, according to analysis done by Revgenetics lab. I’ve since talked to two of the people who have been involved in telomerase products since the beginnings at Geron Corp. One told me that TA-65 is a “sister molecule” to cycloastragenol. The other told me his lab had tested both TA-65 and cycloastragenol for ability to promote telomerase in cell cultures, and that TA-65 was (weakly) positive while cycloastragenol was negative. Meanwhile, scientists at TA-Sciences say that TA-65 contains a single active ingredient, which they will not identify, though they say it is not cycloastragenol. The label refers to a patent 7846904, which covers cycloastragenol, astragaloside IV, and several other related molecules.
  • Product B was developed by Sierra Sciences, and is sold by Isagenix. The formula is based on silymarin, and contains many other herbs, listed here. Many of these ingredients are associated with credible health claims. (I’ve recently become interested in N-Acetyl Cysteine, which is a precursor to the endogenous antioxidant glutathione.) But the particular formulation seems to be based on art rather than science.
  • Stem Cell 100.  The company’s web site features data from a study of flies which lived twice as long when fed Stem Cell 100. The same web page lists 9 herbal ingredients of Asian origin, including astragalus and green tee and several that are less well-known, and which I have not yet had time to research. I haven’t been able to find reference to a peer-reviewed publication of the impressive result with flies, but many other studies of individual herbs are listed on the company’s research web page.
  • T-Activator 100 and T-Activator 200 from Telomere Biosciences are the least documented of these products. I could not find out what is in them, and email to the company’s director has yet to be returned.
  • Centagen seems to be still gearing up.

There is an ongoing discussion of these products at http://longecity.org . Go to Forums → Bioscience, health and nutrition → Supplements → Retail/Product discussion

And for the future?

The best research is being done by Sierra Sciences. They have screened tens of thousands of candidate drugs, and have hundreds of “hits”, meaning that they stimulate cells to express telomerase more powerfully than the astragalus extracts.  With further modifications and development, these chemicals have the potential to keep up with the rate of loss from cell division, and perhaps to restore lost telomere length.  But they are all untested and somewhat toxic. They need to further test these chemicals, tinker with them, see if they can increase efficacy while simultaneously lower the toxicity. Three years from now, we may have a candidate drugs for human trials.

 

*technically, it is in the DNA, but the gene for telomerase is not “expressed”, or turned into the active form.