Metformin, AMPK, and Aging
Nir Barzilai and the TAME study that has major implications for longevity
The key to longevity is balance.
After reading the paper Hallmarks of Aging, which I would say is the hallmark paper of longevity, that was my main takeaway. For the majority of the therapies, whether it came down to stem cell repletion, senescent cell eradication, or inhibition of mTOR, the key was to have the right amount of the given substance. There seems to be a “Goldilocks zone” for every hallmark and the key to longevity is maintain our bodies in that zone for as long as possible.
This principle holds true for AMPK and metformin which is the topic of this article. AMPK is one of the “big three” longevity pathways along with mTOR inhibition and sirtuin activation. They all play a big role in metabolic functions in the cell and they are key “nodes” many biological pathways.
Alteration of these nodes is a good way to extend lifespan as shown in many studies on model organisms like C.elegans, and mice. Small molecules that target these three proteins have had the lion’s share of focus in the longevity world.
What is AMPK and What Does it Do?
AMPK otherwise known as AMP activated kinase is a key node in the pathway in how cells regulate metabolism based on nutrient availability. AMPK is known as the “guardian of metabolism” for its importance.
AMPK does this by sensing the AMP : ATP ratio. ATP as we all know is the energy currency of the cell which is largely produced in the mitochondria or the “power plant of the cell”. When ATP is used it is broken down into ADP, which can further break down into AMP. When there is a high concentration of AMP relative to ATP it means that cellular energy levels have gone down. AMPK can sense when this occurs because it has a binding spot for AMP which would alarm the AMPK when there is too much AMP.
AMPK is a kinase, meaning it can phosphorylate other protiens. The phosphorylation transmits signals to other protiens and can activate them to carry out certain functions. The proteins that AMPK phosphorylates key pathway in metabolism are shown here.
Most Important Functions
- inhibits mTOR → tells the cell to stop growing
- activates ULK1 → activates autophagy(breakdown of cellular/organelle junk)
- activates ATGL→ fatty acid catabolism (breakdown)
- inhibits ACC→ stops fatty acid synthesis
- inhibits HMG-CoA reductase → stops cholestorol synthesis
- activates TBC1D1 → more glucose uptake + glycolysis
The diagram above showcases all of the different ways that AMPK can influence metabolism. What all of these pathways have in common though is that the promote catabolism : the breakdown of materials in the cell. Opposite of anabolism, which is the build up of things in the cell, AMPK acts as like a switch to go into a catabolic state.
Pretty much all the foremost longevity molecules goal is to do this — enter the catabolic state or what David Sinclair calls the “survival circuit”. The position at which most of our bodies are in due to our lifestyle is normally anabolic because of the things we eat, low amount of exercise etc. By pushing ourselves into a catabolic state it forces our body to cut out some of the junk and stay lean.
Caloric restriction, exercise, and hot/cold therapies have been shown to activate this process. But doing those things is hard and requires a lot of effort that not everyone is willing to put in. The key to research today is how can we augment those results with pharmacological agents with higher efficacy.
How Does Metformin Effect AMPK?
You probably know metformin as the drug that is used for type 2 diabetes. Chances are you probably know someone who is on metformin as 78 million Americans were prescribed the drug in 2017. In type 2 diabetes, metformin is used to increase insulin sensitivity but research has shown it has effects that can increase longevity as well.
The mechanism of action for metformin works by inducing energy stress on complex 1 of the mitochondria which reduces the amount of ATP levels. With the concentration of ATP to AMP diminished by the metformin which in turn activates AMPK. With AMPK activated all the functions are carried out by the various pathways and the survival circuit is turned on.
Out of all of the potential drugs to extend longevity, metformin has been shown a increased amount of attention due to the large amount of data that has already been collected on its usage. Scientists have looked at longitudinal human data to examine metformin’s effect on lifespan which other drugs simply do not have.
Unlike the other molecules, metformin has been used widely for decades and in addition is very cheap to source. There are less safety concerns with metformin and there is less procedural concerns which can take a long chunk of the development process.
This is why one of the most groundbreaking longevity trials is being done with metformin. TAME (Targeting Aging with Metformin Trial) is the first in its kind clinical trial that is testing over 3,000 individuals. It is spearheaded by Nir Barzilai of the Albert Einstein College of Medicine and one of the most important people in the longevity field. What is most important about this study is that if it succeeds, it will be the first clinical trial approved by the FDA that includes aging as the indication.
The TAME study will pave the way for more aggressive therapies like senolytics and rapamycin to have large scale clinical trials like TAME. Metformin likely will not add many years to total lifespan (~2 years), but the progress of this study will open the gates for bigger and better ones.