Graeme Jones

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Want To Take The Long Road and Live to 100? Exercise and Calorie Restriction May Just Get Your There

Imagine going on a long road trip in your car without knowing how much fuel you have left in the tank. How do you know when you need to stop for petrol? What does this have to do with aging I hear you ask? Let me explain.

In much the same way as you need to know what is going on with your car, your cells need to know what is going on too. They need to know how much energy you have as well as if nutrients are available to make energy. This helps them determine which functions are best at that particular
time. For example, if they are low on energy and nutrients, they may need to recycle old components that are damaged or that they are not using at that given time.

There are many different nutrient sensing pathways in our cells. Simply put, they detect if food is available or not, and they all interact to help optimise cellular function. As mentioned in my last blog on mTOR, these nutrient sensing pathways play an important role in healthy aging and promote longevity (a longer, healthier life). Another nutrient sensing pathway that interacts with mTOR is called AMP-activated protein kinase, or AMPK.

AMPK works by sensing the energetic state of the cell and is our in-built fuel gauge. Just like your car may use petrol as a fuel source, our cells use adenosine triphosphate (ATP) as an energy currency.
When your car is getting low in fuel, the warning light comes on and you have to stop and refuel. Our body is much more advanced than a car in regard to refueling – it can increase cellular ATP levels to keep us on the road without having to stop.

Activating AMPK for Longevity

During low energy/ATP states, our cells activate AMPK to increase ATP levels, our energy fuel. The first step in the process is to increase the uptake and use of sugar and fats within the cell. Another equally important step is to shutdown processes that use a lot of energy/ATP. No need to waste
efforts on long-term processes if you need to survive the short-term! Finally, the cell breaks down components through a process called autophagy, a recycling type process, making proteins available for energy metabolism. This is like breaking down pieces of your property that are not essential or
not working properly to keep a fire burning that is keeping you warm.

It may sound simple enough, but how does this process play out to promote longevity? Looking back on the 9 hallmarks of cellular aging , quite a bit.

Activating AMPK:
· Stimulates the recycling process called autophagy to remove broken parts from the cell and initiate repair (1)
· Induces mitophagy, recycling of our mitochondria, which is where our ATP/fuel is made – lookout for more on this topic in the future.
· Maintains stem cell pools (stem cells are young cells that can be used to replace old dysfunctional cells). This is like having a garage of spare parts for your car that can be changed out for broken ones when needed.
· Prevents cellular senescence (2). Cellular senescence is when your cells go into a zombie like state and cause inflammation. The senescent cells have been damaged and cannot work but are also not recycled. They are stuck in this state which damages other cells around them. Imagine your car broken down and spilling oil and fuel into the road, causing the arrival of emergency services, and obstructing other vehicles trying to get into a major city. This is like cellular senescence.
· Maintains healthy blood glucose (sugar) levels by increasing glucose uptake by muscle. We do not want high levels of sugar in the blood (this is called diabetes when it continuously happens). AMPK also decreases gluconeogenesis (sugar creation) in the liver – this also helps to reduce risk of higher blood sugar levels.

Now we are understanding that a faster rate of aging occurs when these processes in the bullet points above do not happen regularly enough. For example, having high blood sugar levels/diabetes increases our risk of an early death.

So the pertinent question now becomes, how do we activate AMPK? Not surprisingly, both exercise and calorie restriction activate AMPK. At Nordic Clinic we like things that are free, come with low risk and are good for us. These two activities certainly put a check in those boxes. Interestingly enough, the diabetes drug metformin and the nutritional supplement berberine also reduce glucose output from the liver. Metformin especially is starting to be seen as a possible longevity drug. However, medical drugs and even some supplements come with possible side-effects and may not be right for everyone, so always talk to your doctor before using. Activation of AMPK inhibits mTOR, which from the previous blog we found out is also a good thing for healthy aging. mTOR inhibition is necessary to complete the switch from anabolism (building up) to catabolism (breaking down).

Metformin May Not Be the Key to Longevity in Healthy Individuals

To summarise, AMPK is yet another important nutrient sensing pathway that promotes healthy aging by detecting how much nutrition is around. By sensing the energy status of the cell, sort of like our own fuel gauge, AMPK plays an important role in maintaining healthy cells. It does this by
removing damaged components, preventing senescence (this zombie, inflammatory type state), and maintaining a healthy pool of mitochondria (more on these fascinating parts of our biology in later blogs). Additionally, AMPK helps maintain insulin (the key hormone that helps sugar into our cells) sensitivity by increasing glucose uptake into muscle and decreasing liver glucose output. When we have better insulin sensitivity, we have reduced risk of diabetes.

Interestingly, metformin is currently in clinical trials as a therapeutic to promote healthy aging due to its effects on AMPK. Of course, not everyone wants to exercise and calorie restrict, so could this be the answer? It’s important to point out that while metformin may have beneficial effects on aging in people with Type 2 diabetes, it actually inhibits the beneficial effects of aerobic exercise (running, cycling, swimming etc) in older adults by altering mitochondrial adaptations (3). This means that if you are healthy and exercising regularly, taking metformin may actually harm your mitochondria (parts of your cell important for immune and energy production).

Thus, the beneficial effects may differ between individuals and their chosen lifestyle i.e. if you are overweight and borderline diabetic and not prepared to change your exercise and eating habits, then metformin might be better for you. If you are active, eating well and using some kind of calorie restriction, then use of metformin might actually harm you. Of course, I hope you choose the lifestyle road – there are many
more benefits to also be had.


  1. https://pubmed.ncbi.nlm.nih.gov/30895648/
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257130/
  3. https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12880



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