Metformin Guide - Longevity and Hormone Balance

 

This is a bit off the beaten path for us as we spend 100's of hours studying the pathways that CBD affects.

Along that course of research, we keep coming across really fascinating studies on Metformin, the medication originally discovered for diabetes.

Wait till you see the effects on Akkermensia, the rock star gut bacteria for weight loss and insulin/glucose - the target for most if not all major currenty longevity tools.  (okay...that's a teaser).

 

Our initial interest was due to studies on metformin's effect on hormonal imbalance (the reason we started all this research to begin with).

After all, my perimenopause was a 2-year train wreck that almost did me in (that story here).

It kept popping up for PCOS or polycystic ovary syndrome - a result of hormone imbalance.

Why on Earth would a diabetes medication have an effect THERE?

By the way, hormone balancing is a ridiculously complex job during any period of your life much less when perimenopause is in full bloom (to flip the worldview there).

Only the endocannabinoid system has been shown to balance other key systems like hormones.

Is there a connection there?

Then, another study came out that's probably as revolutionary as CRSPR if you're into longevity.

You know...living longer and living better.

That study showed that metformin was involved in actually REVERSING epigenetic aging.

Another then followed.

Goodness...we're going to have to do a deep dive on this.

Buckle up...periscopes down!!

We'll cover these topics: 

• What is metformin
• How does metformin work in the body
• Metformin and AMPK
• Metformin and glucose and insulin
• Metformin and cancer
• Metformin and pain
• Metformin and the heart
• Metformin and hormones
• Metformin and polycystic cyst syndrome
• Metformin and perimenopause
• The metformin study on epigenetic aging
• The second study on metformin with DHEA
• Metformin and gut bacteria
• Metformin and weight
• Metformin safety
• Metformin and Vitamin B12
• Metformin and Vitamin D
• Metformin and Mitochondria
• My experience with metformin
• How do I get my doctor to write a prescription for metformin
• Metformin versus Berberine

 

We're taking metformin after parsing the aging study and for perimenopausal symptoms so no stone left unturned!

Let's get started.

What is metformin?

Metformin's been around for a while.

It was originally discovered in 1922.

It initially found its calling (added to the World Health Organization's List of Essential Medicines) for diabetes and blood sugar.

Its effect on PCOS and infertility were then discovered.

Finally, new studies are pointing to powerful effects on aging.

The primary pathways are as follows: 

• AMPK
• Mitochondria respiration
• Gut bacteria 
• Hormone balancing
• Epigenetic aging

 

We're going to unravel all of these below.

Looking at the widespread effects of metformin across very different systems, it argues for an adaptogenic effect like curcumin.

The hormone effect alone is very fascinating.

So...how does metformin work in the body?

How does metformin work in the body?

You can find lots of general information on metformin's role (reduced glucose, insulin sensitivity, etc) but clearly, there's more going on.

We're going to show how all this comes together but first, metformin triggers a powerful pathway in the body.

Let's call it the "Winter is Coming" pathway.  We just made that up on the fly.

Basically, it's a survival mode for all sorts of bad times. 

• Starvation (calorie restriction)
• Loss of oxygen
• Drop-in energy
• Stress

 

All the other "side effects" below stem from this one core pathway.

Evolutionarily, it's all about reproduction (isn't everything in nature!).

Think of it this way.

A few million years ago, our ancestors are out on the savannah.

It's a drought and things are dire.

We're probably not going to have offspring this year as a result.

We're lucky just to survive ourselves.

Evolution has a built-in mechanism to "conserve" for next year as a result of the harsh conditions.

"You still need to procreate!!".

We'll keep you around for another year.

There's a huge shift in how the body processes energy.

It's like a company going lean for a recession to survive out the other side.

This is a game of survival but not for you...for your genes!

Selfish little genes.

When energy supply is low, organisms respond by slowing aging and increasing resistance to diverse age-related pathologies.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287273/

Nature wants to keep you around for another mating season since things are tough right now.

That all sounds great and poetic (especially the Winter is Coming thing we came up with) but where's the science to back it and how does metformin enter the savannah?

Let's introduce AMPK.  Your new best friend (for a famine).

Metformin and AMPK 

The primary effect of metformin is an increase of AMPK pathways.

Researchers have even targeted how it does this via actual cellular machinery:

Our current study unequivocally demonstrates that metformin activates AMPK through an ‘‘active’’ process, but not a mere consequence of disruption of metabolic processes such as ATP synthesis through the oxidative phosphorylation 

https://www.cell.com/cell-metabolism/pdf/S1550-4131(16)30481-8.pdf

Do you want to get really technical?

Our finding thus demonstrates that metformin not only activates AMPK but also inactivates mTORC1 through the AXIN/ LKB1-v-ATPase-Ragulator pathway

 

All we need to know is that metformin directly increases AMPK activity.
So...what does that mean?

AMPK is the star of THIS show. 

What is it?  We did a huge review on it here but more below.

It's the manager of energy...both system-wide and at the cellular level: 

AMPK is a highly conserved master regulator of metabolism, which restores energy balance during metabolic stress both at the cellular and physiological levels. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553560/

It's a sensor for how energy levels are going in the body.

Based on its continuous monitoring, it can flip switches downstream for a host of different effects.

Look..we share this AMPK pathway with all living things with DNA and cells except for bacteria.  

It's a powerful and essential tool for evolution.

AMPK is the primary judge between pro-growth (also pro-damage) and conservation (pro-repair) based on signals it receives.

 

In general, boosting AMPK activity will result in conservation.

There's a slew of positive health benefits in today's modern world that go along with that: 

• Leaner metabolism (sugar, energy, inflammation, lipids, weight, etc)
• More efficient cellular activity (cancer, cellular housekeeping, cardiovascular, etc)

 

Let's start to look at the knock-on effects of metformin's boosting of AMPK in the body and brain. 

We'll start where IT started...in the blood sugar and insulin realm with diabetes.

Metformin and glucose and insulin 

As part of AMPK's "rainy day fund" approach, there's an immediate effect on energy metabolism and balance.

In fact, this is AMPK's key role in the body.

Sensing energy needs and then triggering actions accordingly.

It literally acts as middle-person between ADP and AMP...the two basic "pieces" of energy that power everything!

The effects are far-reaching: 

In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, activation of adipocyte lipolysis, and modulation of insulin secretion by pancreatic beta-cells 

https://www.cell.com/molecular-cell/pdf/S1097-2765(17)30396-9.pdf

Look at some of those deciphered and see if they're an issue in our modern world: 

• Liver function with fats
• Sugar levels and use
• Cholesterol processing
• Fat creation itself (lipogenesis)

 

Obesity.  Diabetes.  Cardiovascular risk.  

Slightly relevant.

The knock-on effect of all of these is system-wide inflammation and the net result of that…

Autoimmune disease.

80% of autoimmune diseases are for women and there's a significant risk following perimenopause.

 

Check out our full review of CBD and autoimmune for an in-depth review.

Why?

Maybe this: 

Oestrogen acts by non-genomic means to increase the activation of AMPK that may reinforce some direct genomic actions.

Research is here.

 

 

Goodness...as we lose estrogen, we lose AMPK stimulation.

Again, metformin was and is primarily a medication for glucose and insulin balance.

Check out CBD and inflammation or CBD and neuroinflammation to understand why inflammation causes a range of health issues with perimenopause.

One of those risks (albeit a severe one) is cancer.

Metformin and cancer 

During our research, one point really stood out.

The powerful effects metformin had on many disparate types of cancer.

Both once diagnosed and as a form of prevention!

Simply put: 

In vivo and in vitro studies have revealed that metformin has a direct antitumor effect, which may depress tumor proliferation and induce apoptosis, autophagy and cell cycle arrest of tumor cells.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772929/

What on earth is going on here?

Stay with us...we'll decipher this afterward: 

Studies have demonstrated that reducing insulin and insulin-like growth factor levels in the peripheral blood circulation may lead to the inhibition of phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin (mTOR) signaling or activation of AMP-activated protein kinase, which inhibits mTOR signaling 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772929/

Stick with us...we'll translate.

Two very important pieces.

• First...a reduction in mTOR (rapamycin)
• Secondly, AMPK inhibition of mTOR

 

Rapamycin is the new "longevity" drug and you probably know it from the big resveratrol buzz earlier (with the red wine craze).

It's back in the spotlight again.

AMPK, we already know.

What about mTOR?

mTOR stands for the mechanistic target of rapamycin.

Simply put, mTOR is at the center of deciding which cells live and which cells die.

Why would AMPK interact with this pathway?

In a time of conservation (lean times), efficiency is king.

Senescent or poorly functioning cells are a luxury you just can't have when trying to survive.

Essentially, AMPK ramps up the culling of dead weight via mTOR inhibition (reduction).

Survival of the fittest (cell).

Blocking mTOR has known anti-cancer effects as a result of this. 

Over-activation of mTOR signaling significantly contributes to the initiation and development of tumors and mTOR activity was found to be deregulated in many types of cancer including breast, prostate, lung, melanoma, bladder, brain, and renal carcinomas. 

https://en.wikipedia.org/wiki/MTOR

This article goes into effects across many different cancers but their net analysis: 

Since 2005, metformin has been reported to reduce the risk of cancer by up to 23% worldwide.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497052/

This study from Taiwan: 

For example, the results of the Taiwan National Health Insurance Data Survey, which included a community of 12,005 patients taking metformin from 2000 to 2007 and a population of 4,597 patients taking other oral medications, indicated that using metformin reduces the chance of any type of cancers up to 88%

 

There's a slew of different studies.

Very exciting stuff, especially for perimenopausal women, worried about estradiol supplementation and cancer risk.  

Now that cancer's on the back burner, what about pain.

Metformin and Pain 

This may be the real reason I tried to metformin to begin with.

Yes, a reduction in cancer and revved up AMPK pathways are great but...pain takes precedence when you're in it.

This may sound like a weird effect from the anti-diabetes drug but stay with us.

First, there's a powerful anti-inflammatory effect.

A study looked at metformin following spinal injury in rats: 

Metformin 50 mg/kg improved the locomotors ability (p < 0.001) and decreased sensitivity to mechanical and thermal allodynia 

https://www.ncbi.nlm.nih.gov/pubmed/29959433

Allodynia is a fancy way to say pain threshold.  

The study went on to pin this effect on a reduction in inflammatory agents as a result of the injury: 

While metformin led to weight loss, both metformin and minocycline significantly decreased neuroinflammation in the assessment of cord tissue histopathology, and levels of TNF-α and interleukin-1β (p < 0.001).

 

Oh...and weight loss was a bonus.

Then there's the question of chronic pain.  Like in my heels!

2 years of constant heel pain.  Only topical CBD would touch it but still, it would flare up.

This is where metformin is really interesting.

You have neurons throughout your body there to signal pain.

They can get "stuck" on and overexcited.

This can result in a constant signal of pain even if the original injury (or no injury) has since resolved.

Let's bring AMPK back in. 

AMPK activators also reduce the excitability of these cells suggesting that AMPK activators may be efficacious for the treatment of chronic pain disorders, like neuropathic pain, where changes in the excitability of nociceptors is thought to be an underlying cause 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715474/

This is exactly what I was looking for.  

I had an initial injury but the pain is stuck.

Yes, I had MRI's, X-rays, PT, specialists, nerve testing from back to feet, inserts, specialized shoes, etc.

This was pain...IN the nervous system.

Metformin, and our next target, low dose Naltrexone, appear to work at that level.

Finally, remember how AMPK would dampen mTOR activity from above?

This matters for chronic pain: 

The mTOR complex 1 and its triggered protein translation are required for the initiation and maintenance of chronic pain (including cancer pain) and opioid-induced tolerance/hyperalgesia.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455918/

"Required for initiation and maintenance of chronic pain".

Of course, pain from inflammation and autoimmune diseases are a definite target of metformin and the AMPK pathways since both of those are positively affected.

For example: 

AMPK activation attenuates inflammatory pain through inhibiting NF-κB activation and IL-1β expression

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1411-x

Stay tuned for the low dose naltrexone review on this front.

Next up, the heart.

Metformin and the heart 

Cardiovascular risks are associated with perimenopause and menopause.

This isn't surprising considering the effect of estradiol and progesterone on cardiovascular function.

What can metformin do there? 

Needless to say, insulin sensitivity, glucose function, cholesterol and lipid levels, fat creation, and systemic inflammation reductions from metformin are positive for the cardiovascular system.

 

At a summary level, that all makes sense.

Let's drill down deeper (figuratively) into actual heart function and metformin. 

At the systemic level, possibly also through other pathways, this drug improves endothelial function, protects from oxidative stress and inflammation, and from the negative effects of angiotensin II.  

https://www.ncbi.nlm.nih.gov/pubmed/28709719

Endothelial refers to the smooth muscle lining of veins, valves, and your cardiovascular system.

Oxidative stress and inflammation may be THE key.

 

In fact, it's hard to have deposits in the lining of your arteries without inflammation. 

New research is showing that arteriosclerotic deposits have the DNA of bacteria (from your mouth of all places) and the immune system panics when they escape and locks them away. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024159/

This is an inflammatory process!  The autoimmune process.

Check out CBD oxidative stress or CBD and inflammation.

In fact, studies looking at heart failure (with or without diabetes) are showing powerful effects thanks to AMPK and other pathways: 

By increasing nitric oxide (NO) bioavailability, limiting interstitial fibrosis, reducing the deposition of advanced glycation end-products (AGEs), and inhibiting myocardial cell apoptosis metformin reduces cardiac remodeling and hypertrophy, and thereby preserves left ventricular systolic and diastolic functions. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213955/

Next up...the really important (not to diminish cancer and heart) effect of metformin.

Hormones!

Metformin and hormones  

Check out our perimenopause versus menopause article.

This whole process is about hormones!

Fluctuation and drops in hormones.

What first caught our eye was the secondary use of metformin for polycystic ovarian cysts.

That's a symptom of hormone imbalance which we'll get to in the next section.

Hormones are so complicated, especially during perimenopause.

How on earth could metformin operate in this channel (fraught with danger)?

Remember that AMPK activation is akin to a reproductive rain-check.

Can't make offspring now...just trying to survive (starvation, lack of oxygen, etc).

For this reason, AMPK has a dampening effect on steroidal hormone (estradiol, testosterone, progesterone) production.

This primarily starts at the beginning of the chain where pregnenolone is turned into all the different hormones.  See our full review for pregnenolone.

When looking at women with breast cancer: 

The women receiving 1500 mg/d showed a greater and significant reduction of free testosterone (-29%) and estradiol (-38%), a borderline significant reduction of estrone and insulin-like growth factor-1, and a nonsignificant reduction of androstenedione 

https://www.ncbi.nlm.nih.gov/pubmed/24267731

This isn't the whole picture though as metformin has been shown to help with infertility and help with hormone imbalance related PCOS.

We need more research but maybe this statement is the key take-away: 

AMPK thus acts to preserve cellular energy and prevent excess steroid production. 

https://academic.oup.com/biolreprod/article/87/Suppl_1/11/2956393

The keyword is "excess".

If metformin (via AMPK) only pushed steroidal hormones down, this would infer reduced fertility.

What about studies on women without PCOS since that's an obvious detriment to getting pregnant: 

Ongoing pregnancy rate improved significantly with metformin compared with previous IVF, and pregnancy correlated significantly with a DS at an optimal threshold of 0.6647 (sensitivity, 0.90; specificity, 0.91). Study II. Ongoing pregnancy and implantation rates were significantly higher in women with a DS above 0.6647 who received metformin (56% and 33%)  

https://www.ncbi.nlm.nih.gov/pubmed/20687400

DS was a way to take into account other factors.

Either way, more pregnancy with low dose metformin for women WITHOUT PCOS.

Speaking of PCOS…

Metformin and polycystic cyst syndrome 

For those who don't know, PCOS is when the ovaries will create cysts...little sacs of fluid.

This is usually the result of hormone imbalances. 

The current theory is that insulin pathways lead to increase body fat which results in a hyperactive release of steroidal hormones.  

Hormones imbalances are the signature of this issue: 

Despite the fact that ovarian hyperandrogenism is considered the mainstay of PCOS, 40%–50% of the patients also exhibit elevated adrenal androgens and it is possible that this feature also clusters in families with this disorder. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068665/

There is however, a clear tie with metabolic dysfunction (such as diabetes) and PCOS: 

It has been established that the incidence of metabolic syndrome increases substantially during perimenopause and after menopause [12]. What is interesting, Livadas et al. reported an increase in insulin resistance along with aging, but only in obese women with PCOS  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352911/

So...what does metformin do there?

  

Here's where it gets interesting (pointing back to our hormone section above): 

In women with normal baseline concentration of DHEAS, metformin results in a significant increase of DHEAS by 13%. In contrast in women with high baseline DHEAS, metformin resulted in a statistically significant decrease of DHEAS by 12%. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068665/

Elevated DHEAS is a signature of PCOS.

But wait...when elevated, metformin would drop this level.
When too high, it would LOWER it!

This is fascinating...again, we've only seen this "balancing" effect with the endocannabinoid system.

Next up, elevated testosterone, another signature of PCOS in women (hence the acne and hair growth).

First, what's the connection between insulin and testosterone? 

Insulin infusion studies have shown a clear association existing between serum insulin and testosterone levels in cases of PCOS, suggestive of a cause and effect relationship 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994574/

And what does metformin do there? 

Our study also revealed insulin resistance measured as fasting glucose to insulin ratio to be reduced from 77.27% of cases to 40.1% after metformin therapy, showing an improvement in insulin sensitivity. 

 

What do PCOS and perimenopause have in common?

Imbalances in upstream hormones such as FSH.

With perimenopause, it's the cat and mouse game between FSH and estradiol that sends about 25% of women into a tailspin.

Metformin's effect on FSH?

Another study looked to menstrual periods and in women with PCOS: 

Study results found that BMI, testosterone, free androgen index, luteinizing hormone levels, and luteinizing hormone/follicle-stimulating hormone ratios to be significantly lower after 24 months of treatment when compared with baseline values in both subgroups. 

https://www.endocrinologyadvisor.com/home/topics/androgen-and-reproductive-disorders/metformin-and-pcos-improving-menstrual-cycle-and-hormone-profiles/

This gets to the delicate dance and balance of monthly steroidal hormones.

Their conclusion: 

Researchers concluded that metformin is indeed associated with improvements in menstrual cycle regularity and hormonal patterns in normal weight and overweight women with PCOS placed on metformin drug therapy for 24 months

 

"Regularity and hormonal patterns" is the key there for PCOS and perimenopause.

There are lots of NIH studies like this.

We're most fascinated by the ability to balance hormones.

To wrap it all up in a bow for perimenopause... 

Estrogen deficiency due to natural menopause or surgical menopause has been suggested to have an adverse effect on insulin resistance. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693666/

Who knew that insulin had such powerful effects on steroidal hormones!

One last note before we have to move on.

Progesterone starts to drop late 30's and early 40's.

I started to have ovarian cysts early to mid 40's out of nowhere.

What's the relationship between progesterone (not synthetic progestins) , PCOS, and metformin: 

The study further demonstrated a significant enhancement in luteal progesterone concentration (16.97 ng/ml) in PCOS women treated with metformin. 

 

Fascinating since low progesterone is suspect in PCOS itself.

We did a giant review of progesterone and immune function here.

Next up, perimenopause.

Metformin and perimenopause 

As we established in our perimenopause versus menopause or estradiol review, perimenopause is a period of intense hormone change and the resulting knock-on effects are everywhere.

Progesterone starts dropping slowly around 40 and continues on down in a steady fashion.

Estradiol can go through intense peaks and valleys like a roller coast during perimenopause.

That volatility is the basis for the symptoms associated with this change.

And of course, the eventual drop that leads into menopause.

Let's look at perimenopause in a different way.

First, the role of AMPK is cellular conservation for better days.

Really, it's about putting reproduction off till the chance of survival is higher.

Remember, our basic wiring is 10's of thousands of years old (and AMPK goes back to the beginning of cellular life).

Old rules die hard.

First...what happens to AMPK during perimenopause when reproduction is no longer on the table?

Interestingly, big changes can be seen in the transition from regular to irregular cycling (the earliest part of perimenopause...maybe years in advance of the official 12-month loss of period): 

The decline in Bioenergetic Enzyme Expression Was Accompanied by Inhibition of the Insulin/IGF1 and AMPK Signaling Pathways in Hippocampus during the Regular-Irregular Transition

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416218/

Ladies, this may sound complex but that study goes through a litany of very important pathways that start to turn down with perimenopause.

Next time your doctor says your depleted estradiol and progesterone levels are normal for your age….find another doctor.

There's a whole section about the decrease in "brain plasticity" which is the root of anxiety and depression.

Check out estradiol's powerful effect at CBD and perimenopause anxiety or CBD and perimenopause depression.

Speaking of estradiol...what is its role in AMPK levels?

Let's follow the breadcrumbs.

First...estrogen and insulin: 

Estrogen deficiency, due to natural menopause or surgical menopause, has been suggested to have an effect on insulin resistance 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693666/

That is one of the primary switches of metformin via AMPK.  hmmmm.

Does estradiol directly affect AMPK?: 

Low concentrations of E2 (10 and 100 nmol/l) were found to increase AMPK phosphorylation by approximately 1.6-fold, while a higher concentration (10 micromols/l) resulted in an approximately 3.0-fold increase.  

https://www.ncbi.nlm.nih.gov/pubmed/18421261

And estradiol is leaving the station. Perhaps, metformin can be the next train!

Now, on to our favorite new area of research on metformin.

The metformin study on epigenetic aging 

People, this may be the biggest news since CRISPR (gene editing).

We'll link directly to the study but here's the quick run-through (of a very technical and sophisticated piece of research).

Essentially, the researchers establish how the thymus (just above and behind your breastplate) is a key controller for the aging process.

They wanted to see if there was a way to offset the age-related shrinking of this powerful gland to stop aging.

Epigenetic aging to be exact.

Look, your genes are not much different now than when you were 25 or even 25,000 years ago.

The difference in how you look/feel now versus then mainly comes from your epigenetics.

This is a layer of activity that sits on top of your genes and turns then on and off.

Your genes are the keys of a piano.

The difference between Row, Row, Row your Boat and Rachmaninov is the pattern in which they're played.

That's epigenetics!

So….the researchers used growth hormone, metformin and a cancer drug to try to stop the thymus from withering further.

It worked!

In a 12 month course, it reversed the epigenetic age 2.5 years. 

The crazy part is that towards the last 3 months, it was reversing at a 6.5-year clip!

What does that mean??

Your biological age is different from your epigenetic age.

Some people live hard and their body shows it.

That's epigenetic age.

A review of the study is here: 

https://www.nature.com/articles/d41586-019-02638-w

Now, not everyone has access to growth hormones so we're using arginine/ornothine (amino acid precursors) which you can get here.

Metformin requires a prescription and you would be surprised how difficult doctors can be about this outside of glucose issues.

Benzos, Opioids,  and SSRI's are just fine though.

Berberine might be an alternative and you can get that here. 

Metformin was actually used to offset cancer risk from the growth hormone after all.

 
Let's switch it up a bit.

 

The second study on metformin with DHEA 

A very recent study from UCLA tried a different mix and the results: 

The people were 1.5 years younger according to epigenetic markers than when they were first measured one year prior. The trial included two widely used anti-diabetic drugs, dehydroepiandrosterone (DHEA) and metformin, in the treatment cocktail. 

https://www.nextbigfuture.com/2019/09/2-5-years-of-aging-reversal-from-metformin-and-dhea.html

DHEA is a steroidal hormone with powerful effects of its own.

Check out our review of pregnenolone which turns into all the steroidal hormones including DHEA.

The one thing these two studies with similar results have in common…

Metformin!

It appears to help reset our immune system via the thymus and that may be the weak link in our aging process.

The first link is.

By the way, AMPK is the same pathway that other known longevity pathways use: 

• Calorie restriction
• Exercise
• Hypoxia - loss of oxygen

 

All big promoters of AMPK and all directions affecting aging.

This brings up another player in this longevity pathway.

SIRT1.

Metformin and SIRT1 

Speaking of immune function, we have to look at inflammation.

This ultimately leads us to the first star in the longevity space.  Sirtuin or SIRT1

How does it fit into this? 

Human aging is characterized by a chronic, low-grade inflammation level[18] and NF-κB is the main transcriptional regulator of genes related to inflammation.[19] SIRT1 inhibits NF-κB-regulated gene expression by deacetylating the RelA/p65 subunit of NF-κB at lysine 310 

https://en.wikipedia.org/wiki/Sirtuin_1

And the relationship with metformin…

Metformin activates both PRKA and SIRT1.

This is part of Metformin's powerful effect on inflammation.

There is research showing a wide-range effect on many inflammatory agents, some of which are quite fascinating: 

Following up on these findings in a double-blind placebo-controlled trial in nondiabetic heart failure (trial registration: NCT00473876), metformin suppressed plasma cytokines including the aging-associated cytokine CCL11 (C-C motif chemokine ligand 11). 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990459/

Did you catch that…"aging-associated".

They found these effects were separate from its impact on insulin.

To understand the importance of inflammation, check out CBD and elderly anxiety or CBD and long term anxiety.

Let's move further south.  To the gut!

Metformin and gut bacteria (Akkermensia connection)

New research on almost everything is pointing to the gut bacteria or microbiome.

Why should metformin be any different?

The basic premise of reducing sugar production in the liver isn't the whole story.  We did a giant review of how sugar causes so much damage in terms of aging.

As we discussed above, AMPK is the workhorse behind metformin's many effects.

But there are also big changes in the microbiome: 

In particular, the drug seemed to encourage the growth of strains of bacteria called Akkermansia and Bifidobacterium. Lab experiments revealed that both types also grew faster in the presence of metformin. 

https://www.newscientist.com/article/2132009-diabetes-drug-may-work-by-changing-gut-bacteria-makeup/#ixzz623zBgcOv

We know Bifido all too well since histamine is an issue for us (as for most women in perimenopause).

Akkermansia, however, is very interesting.

Some key takeaways which should shed light on its tie with metformin: 

The study was carried out with mice, overfed to contain three times more fat than their lean cousin. The obese mice were then fed the bacteria, which were shown to reduce the fat burden of the mice by half without any change to the mice's diet. 

https://en.wikipedia.org/wiki/Akkermansia_muciniphila

Think about this...the mice were fed significant amounts of food but if they were given this particular gut bacteria, it reduced fat accumulation by half!

This lead to the New York Times headline:

A Probiotic for Obesity?

 

Recent studies mirror this effect in humans on multiple aspects: 

Compared to placebo, pasteurized A. muciniphila improved insulin sensitivity (+28.62 ± 7.02%, P = 0.002), and reduced insulinemia (−34.08 ± 7.12%, P = 0.006) and plasma total cholesterol (−8.68 ± 2.38%, P = 0.02). Pasteurized A. muciniphila supplementation slightly decreased body weight (−2.27 ± 0.92 kg, P = 0.091) compared to the placebo group, and fat mass (−1.37 ± 0.82 kg, P = 0.092) and hip circumference (−2.63 ± 1.14 cm, P = 0.091) compared to baseline.  

https://www.nature.com/articles/s41591-019-0495-2

All with a strong safety profile.

People...we are spending billions on drugs for: 

• Diabetes (28% improvement in insulin sensitivity)
• Cholesterol (9% reduction) without muscle wasting
• Weight loss (over 2 pounds in initial period)
• Fat mass and hip circumference

 

This study was only for 3 months.  Imagine a decade of this.  Pendulum has a pretty good probiotic around Akkermensia here.  

As for the safety profile...awesome.

After all, in healthy people, this class of bacteria makeup 3-5% already

NOT in people with diabetes or obesity, however!

To tack on another few billion in lost pharma sales, what about the autoimmune response.

This akkermansia was found to thicken the gut barrier as well: 

The positive modulation of mucus thickness and gut barrier integrity by A. muciniphila could be the key to its aforementioned probiotic activities.

 

Look...bacteria escaping your gut, landing somewhere (joints, brain, arteries, etc) is the basis for autoimmune diseases.

See our reviews on gut barrier and autoimmune.

Diagnosis for autoimmune lands 80% on women!!!

The gut barrier is key to this and akkermansia's effect: 

A. muciniphila supplementation was able to restore mucus thickness in obese and type 2 diabetic mice where gut mucus was disrupted by high-fat diet treatment; the treatment also resulted in a significant reduction of serum lipopolysaccharides (LPS), metabolic endotoxemia, and improved the metabolic profile 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223323/

We're geeking out!

LPS is bacteria that escaped the gut.

This one effect may be reason enough for metformin use even in prevention!

Dementia.  Alzheimer's.  Diabetes.  All being re-evaluated as Autoimmune in nature.

Check out our article on CBD for neuroinflammation to understand how the microglia (our brain's immune responders) can run amok and actually attack our neurons.

 

 

Metformin's effect on this: 

The results revealed that metformin significantly attenuated several inflammatory responses in BV-2 microglial cells, including the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin (IL)-6, involved in the activation of Beclin-1, a crucial regulator of autophagy.  

http://www.bslonline.org/journal/view.html?uid=1027&&vmd=Full

Other studies have found a range of gut effects from metformin and its anti-inflammatory effect here: 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023991/

Check out CBD and probiotics for anxiety or CBD and the microbiome.

All of this brings us to the next section.

Metformin and weight 

We just saw a big effect on obesity and weight from the gut bacteria changes of metformin.

Same calories - half the fat accumulation.

 

At first, researchers thought that the weight loss effects of metformin were solely due to the sugar and insulin effect.

More recent studies know better (what you know now!): 

Emerging evidence suggests that metformin-associated weight loss is due to modulation of hypothalamic appetite regulatory centers, alteration in the gut microbiome, and reversal of consequences of aging. 

https://www.ncbi.nlm.nih.gov/pubmed/30874963

Weight gain is a huge problem during perimenopause.

Just check out our review for CBD and perimenopausal weight. 

Studies are showing modest weight loss with metformin combined with reduced risk of diabetes and other metabolism-related issues: 

Adults using metformin experienced and maintained small decreases in weight irrespective of the duration of intervention. In 11 of 14 studies, a greater reduction in weight/BMI was observed with metformin than with placebo. 

https://www.ncbi.nlm.nih.gov/pubmed/30511324

What about for non-diabetic people?: 

The mean weight loss in the metformin-treated group was 5.8±7.0 kg (5.6±6.5%). Untreated controls gained 0.8±3.5 kg (0.8±3.7%) on average. Patients with severe insulin resistance lost significantly more weight as compared to insulin-sensitive patients. 

https://www.ncbi.nlm.nih.gov/pubmed/23147210

Almost 6 pounds.  

It's not just fat accumulation though.

Metformin and appetite

Hormones are powerful things.  In fact, they govern when we're hungry and when we feel full.

The term is anorexigenic or causing a loss of appetite.

We'll settle for a reduction in chocolate. (check out the connection between CBD and chocolate).

What does metformin do there!

Results showed that the central administration of metformin significantly reduced food intake and body weight gain, particularly after 4 hours. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146045/

Newer studies can now drill down to the exact mechanism.

For example, one study in mice found: 

In DIO but also in DR rats, metformin treatment induced significant reductions in food intake accompanied by decreases in body weight.

 

DIO is short for diet-induced obesity - overfed essentially.
DR is diet-resistant

In both groups, they pinpointed how metformin was affecting appetite.

These data identify the hypothalamic ObRb as a gene modulated after metformin treatment and suggest that the anorectic effects of the drug are potentially mediated via an increase in the central sensitivity to leptin.  

https://www.ncbi.nlm.nih.gov/pubmed/20303124

Leptin is your "I'm full" hormone.  The one depleted after the loss of sleep or too much stress.

Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite.

https://www.semanticscholar.org/paper/Brief-communication%3A-Sleep-curtailment-in-healthy-Spiegel-Tasali/caf26bffc40054205a31a17d32c82ebe9d90b8cc

Let's drill down further to the real source of "hungry".

Leptin keeps another substance Neuropeptide Y down.  Why is that important?

NPY is a potent orexigenic agent and is presumed to play a leading role in the regulation of eating behavior.  

https://www.ncbi.nlm.nih.gov/pubmed/10681656

NPY say "I'm hungry NOW!!"

Activity of the NPY-ergic ARC-PVN pathway is suppressed by leptin - a polypeptide produced by adipocytes.

 

So...if your head is spinning and you're about to reach for that bag of chips: 

• Metformin improves leptin sensitivity (which gets used up in our modern diet)
• Leptin keep NPY in check
• Appetite drops

 

The study that started all this above looked at actual genes turned on and off in the hypothalamus to get to this.

Goodness!

There's a pretty good walk through this whole energy balancing system here: 

https://www.huffingtonpost.com.au/2017/04/20/so-this-is-exactly-how-sugar-makes-us-fat_a_22046969/

How does metformin get into the mix?

Insulin.

Basically, too much sugar creates too much insulin which burns out the leptin "sensors" in the hypothalamus.

It just stops responding which is to tell the brain the we're full.

In fact, there's a significant effect on weight by correcting this insulin imbalance: 

We examined changes in REE and leptin in a cohort of 17 obese subjects during experimental weight loss therapy with the insulin-suppressive agent octreotide-LAR, 40 mg i.m. q28d for 6 months. Six subjects lost significant weight (>10%) and BMI (>−3 kg/m2) with a 34% decline in leptin and a 46% decrease in insulin area under the curve (IAUC) to oral glucose tolerance testing 

https://www.nature.com/articles/0802753

To end this section (sorry for the length but this is important stuff)...

Metformin's effect on insulin is its primary lever.

It reduces sugar creation and improves insulin sensitivity as a result.

We've looked at many benefits.

What about the safety?

Metformin safety 

If Tylenol is the leading cause of liver failure in the US, we're not sure how metformin isn't available over the counter.

Metformin has been prescribed to 100's of millions of people worldwide.

The list of side effects are here but the primary complaints are GI issues. 

https://www.rxlist.com/consumer_metformin/drugs-condition.htm

We saw above why this might be the case. 

Metformin is literally remodeling your gut microbiome but for the better!

Any big change to microbiome ratios will result in gas and other GI issues.

One strain may die off while another explodes in numbers.

These issues should go away one the gut reaches equilibrium (it is zero sum gain after-all...only so much GI tract).

The other issue to look at is acid lacidosis...an excess amount of lactate.

It's exceedingly rare.

One study looked at 347 trials with 70,000 metformin users and compared their lactate levels to 50,000 non-metformin users: 

Average lactate levels measured during metformin treatment were no different than for placebo or for other medications used to treat diabetes.  

https://www.cochrane.org/CD002967/ENDOC_risk-of-fatal-and-nonfatal-lactic-acidosis-with-metformin-use-in-type-2-diabetes-mellitus

Not one case!

So why all the scary language and warnings on traditional sites that are running Januvia (costs around $500/month and has a robust list of side effects) ads?

Not sure.

In people with significantly impaired kidney function, lactate can build up.  

There must have been cases somewhere at sometime.

It's at under 10 cases per 100,000 people and mainly tied to people with diabetes (due to resulting kidney damage).

The FDA warning indicates for people with "severe renal (kidney) impairment".

To put it to rest: 

Lactic acidosis is a rare complication to type 2 diabetes mellitus (T2DM), with an incidence of 6/100,000 patient-years. The risk is not increased in metformin-treated patients. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079480/

Run a simple test after to see how your lactate and kidney function looks.

Personally, I'm taking 500 mg (probably will go up to 850 mg) which is at the low end.

Again, you go on any mainline website and they'll warn about fatal risk of acid lacidosis.

We need a revolution!

Here's a good walk through some of the common boogaboos: 

https://www.goodrx.com/blog/ten-myths-about-metformin/

Let's look at three more specifically that were important to us and generally float out there in the medical field.

Metformin and Vitamin B12 

B12 is dear to our heart as I have MTRR and my spouse has MTHFR which means that we don't process folate or B12 well.

There were some initial studies showing that metformin might interrupt B12 absorption in the gut.

Again, the studies are primarily looking at long term use with people that have diabetes.

For example, one study: 

The prevalence of B12 deficiency was 7.8% overall, but 9.4% and 2.2% in metformin users and non-metformin users, respectively. 

https://www.ncbi.nlm.nih.gov/pubmed/30321183

In terms of the net effect on neuropathy (B12 is needed for building nerve protective sheath): 

There were no significant differences in a test of peripheral neuropathy between the metformin users and non-metformin users

 

Higher does and longer terms were tied to this result: 

Low levels of vitamin B12 occurred when metformin was taken at a dose of more than 2,000 mg/day (AOR, 21.67; 95% CI, 2.87-163.47) or for more than 4 years (AOR, 6.35; 95% CI, 1.47-24.47).

 

So..what do we do!

Supplement with methylated B12 (and folate).  Really all the B's are critical.

I use a sublingual methylated B12 which you can get here.

While you're at it, check out you're MTRR and MTHFR status at 23andme or Seeking health.

40% of the population has these mutations and these pathways are critical!

Metformin and Vitamin D 

This comes up although for the wrong reason.

First, there was no impact to metformin use on Vitamin D levels or Vitamin D supplementation: 

No statistically significant difference was found between users and nonusers of metformin in regard to 25(OH)D levels when adjusted for variables (P = .297; 95% CI for mean difference = -0.7 to 2.2 ng/mL). 

https://www.ncbi.nlm.nih.gov/pubmed/21940283

Some studies found that D and metformin together may help with its anti-cancer effect.

Another important piece..mitochondria.

Metformin and Mitochondria 

We've discussed AMPK quite a bit.

Another key pathways deals with mitochondria, the little power plants of our cells.

Metformin has been shown to reduce energy production in the first step called complex 1.

How big is the effect? 

Importantly, metformin only exerts a weak and reversible selective inhibition of complex 1 (IC50 ~20 mM), making it a peculiar type of inhibitor that does not resemble the canonical ones like rotenone and piericidin A 

https://www.frontiersin.org/articles/10.3389/fendo.2019.00294/full

This partially speaks to the issue of oxidative stress which can cause so much damage.

Metformin has shown powerful anti-oxidation stress effects and the focus on complex 1 appears to be the reason: 

Superoxide anions are primarily generated by the mitochondria, mostly at complexes 1 and 3 of the electron transfer chain (ETC) where electrons are leaking and could react with oxygen

 

Check out CBD and glutathione or CBD and oxidative stress to understand why this is so important.

 

 

Again, this is probably a net effect of AMPK triggers we described above: 

Recent studies have identified a direct link between AMPK activation and mitochondrial dynamics pathways. 

https://diabetes.diabetesjournals.org/content/67/Supplement_1/157-OR

What does this mean functionally?

Does it mean we'll have less energy?

No...this is cellular efficiency basically.  Waste product management.

For example, newer (more sophisticated) studies are showing the effects of reducing oxidation: 

Metformin Has Direct Protective Effect on Human Cardiac Mitochondria

https://www.fasebj.org/doi/abs/10.1096/fasebj.2019.33.1_supplement.794.4

When things are flush (think Silicon Valley), you can waste money on chefs and free coffee.

When the economy turns, you have cut out the frills and become lean and mean.

That's AMPK and the effects even show in our mitochondria.

How do I get my doctor to write prescription for metformin 

The answer is easy.  

Get diabetes.

Just kidding but…

There's a great deal of push back from doctors and many will act incredulously when you ask for metformin.

Just don't say you read about it online or you'll get that look.

Funny thing is, we ran this by our friend who's a doctor and all the doctors he knew were on it!

Prophylactically (prevention).  

The main angles are as follows: 

• Blood sugar
• Weight
• Cancer
• Pain (they may not know this element of it)

 

A doctor won't write a script for reversing epigenetic aging (although they'll probably run out, research it, and start taking it themselves).

At the RADFest (for longevity), we found a doctor who is working to bring this option to more people via online processing.

We get ours online from agelessRX here.

Otherwise, there's Berberine for now.

Berberine versus Metformin 

If you can't get a prescription for Metformin (aka dark ages), berberine may be our best option.

In fact, there are very similar profiles in action between metformin and berberine: 

Metformin and berberine share many features in actions despite different structure and both could be excellent drugs in treating T2DM, obesity, cardiac diseases, tumour, as well as inflammation.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839379/

What about AMPK...that's our gravy ticket!

Pretty sophisticated research pinpointed its effects to AMPK: 

In conclusion, the results of the present study demonstrate that BBR activates AMPK to induce phosphorylation of SREBP-1c, 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436149/

Studies on berberine actually pinpoint what comes first...mitochondria downregulation or AMPK: 

Berberine-induced AMPK activation is likely a consequence of mitochondria inhibition that increases the AMP/ATP ratio. 

https://www.ncbi.nlm.nih.gov/pubmed/17971514/

Interesting!

You can get berberine here with no prescription and it's been a facet of Chinese medicine for 1000's of years.

We also have the gut bacteria improvement and gut lining thickening: 

One of the biggest changes seen in the microbiome with berberine supplementation is that the quantity of the beneficial bacteria Akkermansia muciniphila in the gut increases. 

https://enzymedica.com/blogs/naturaldigestivehealth/berberine-the-microbiomes-super-booster

Sound familiar?

We'll do a full review of metformin versus berberine as the safety profile of berberine is very strong.

Always supplement the B vits with either.

My experience with metformin 

Metformin has been a game changer for my perimenopause.

Bioidentical hormones, basic supplementation, and CBD all had a role.

The final two pieces were jolts in the middle of the night and intense heel pain.

I felt the effect of metformin within days and had joltless nights for the first time in a few days.

There are some GI side effects but I'll take that over autoimmune disease, cancer, and systemic inflammation.

They went away after about 10 days.

Make sure to supplement and watch the Vitamin B's (methylated ideally).  All the B's really.

Next up, we'll tackle low dose naltrexone which is equally fascinating.

More to come.

Also, make sure to check out the full review on estradiol, Siberian Rhubarb, and of course….CBD.

Be well!

Related Articles:

AMPK guide for longevity

CRISPR and longevity

Pterostilbene and longevity

Carnosine for and sugar damage

 

 

Always work with a doctor or naturopath with any supplement!

The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.