AMPK, Sirtuins, mTOR: Pathways to Longevity


May 25, 2024

Longevity research has identified three important signaling pathways in the body that slow down the ageing process and promote health. They act as energy and nutrient sensors in the body and react to changes in our cells. Each pathway has its own mechanism that regulates bodily functions and the ageing process. All three pathways work together synergistically and are essential for our organism. However, they have different effects on the processes that influence our longevity and on different metabolic pathways. AMPK, Sirtuins, mTOR: Pathways to Longevity.

Sirtuins – the switches of longevity
Sirtuins are special proteins in the body that play an important role in controlling our genes. To understand how they do this, we first need to visualize how our DNA is packaged in cells.
Imagine our DNA as an incredibly long string – if you strung the DNA of all the cells in our body together, it would cover a thousand times the distance from the Earth to the sun! Ultimately, this enormous length has to fit into our tiny cells. To make this possible, our body winds DNA onto tiny “coils” called histones. The DNA packaged in this way is then neatly stowed away in the cells.
This is where the sirtuins come into play. They have the ability to modify the histones, which influences which genes can be read and which cannot. They act like switches that can turn certain genes on or off. This is why they are also known as “epigenetic regulators”.

NAD – without this coenzyme, sirtuins are powerless
However, in order to operate these switches and activate our longevity genes, the sirtuins require a special coenzyme called NAD (nicotinamide adenine dinucleotide). With increasing age, however, the amount of available NAD in the body decreases. Without this essential cofactor, the sirtuins can no longer work effectively and their activity decreases. It is assumed that this is one of the reasons why we become more susceptible to diseases as we age.

AMPK – the energy conductor of the cell
Finally, adenosine monophosphate-activated protein kinase (AMPK) also plays an important role. AMPK is an enzyme in our cells that influences insulin sensitivity and glucose uptake in the cells. It is like a guardian that constantly checks whether our cells have enough energy. When energy becomes scarce, AMPK kicks into action and ensures that more energy is made available.

At the same time, AMPK inhibits the antagonist mTOR (“mechanistic target of rapamycin”), which controls energy production in our cells. If mTOR is too active, the cells use more energy to control anabolic processes. AMPK therefore ensures that our cells use their energy efficiently when food is scarce. However, AMPK does even more for our cells. It helps them extract energy from fats and promotes autophagy, a process in which cells cleanse and rejuvenate themselves.

AMPK and health: the key role in metabolic processes
The activation of AMPK can be influenced by various factors, and there are several reasons why many people have difficulty activating AMPK effectively:

Sedentary lifestyle and lack of physical activity:
An inactive lifestyle and lack of physical activity can lead to insufficient AMPK activation. AMPK is activated by muscle contractions during exercise, but people who do little or no exercise may have reduced AMPK activity.

Unhealthy diet:
An unbalanced diet with an excess of calories, especially carbohydrates and fats, can impair AMPK activation. High-calorie intake, especially from poor sources, can lead to an increase in ATP (adenosine triphosphate) and hinder AMPK activation.

Insulin resistance and obesity:
People with insulin resistance or obesity often have problems activating AMPK. Insulin resistance can disrupt the signaling pathway of AMPK, leading to decreased activity of AMPK. Obesity can also impair the function of AMPK in fat cells.

Ageing process
The aging process tends to lead to a decrease in AMPK activity. This can contribute to older people having difficulty activating AMPK effectively, which can have an impact on metabolism and energy homeostasis. Energy homeostasis describes the balance between supplied and released energy that the body needs for optimal performance.

Genetic factors
Individual genetic predisposition can also play a role in AMPK activation. Some people have genetic variations that can affect AMPK function.

Chronic stress
Chronic stress can disrupt energy homeostasis and inhibit AMPK activation. Stress hormones can affect AMPK signaling pathways, interfering with normal activation. Insufficient activation of AMPK can accelerate the ageing process and shorten life span and especially health span. The diabetes drug metformin and the natural plant compound quercetin can activate the AMPK signaling pathway in the body and improve insulin sensitivity.

How you can activate AMPK
Adenosine monophosphate-activated protein kinase (AMPK) activation can be achieved in a variety of ways, including lifestyle changes, diet, exercise and certain medications. Here are some strategies to activate AMPK:

  1. Regular physical activity
    • Aerobic training: Endurance training such as running, cycling and swimming can activate AMPK as it affects ATP and AMP levels
    • Resistance training: Strength training can activate AMPK, especially in the muscular system
  2. Calorie restriction and interval fasting
    Reduced calorie intake and intermittent fasting (interval fasting) can activate the AMPK signaling pathway as they lead to an increase in AMP relative to ATP.
  3. Healthy diet
    • Low-fat, high-fiber diet, low in saturated fat and rich in fiber, can support AMPK activation
    • Foods that promote AMPK: Green tea, curcumin (in turmeric), Resveratrol (in red grapes) and Omega-3 fatty acids (in fish) can activate AMPK
  4. Metabolic stressors
    Cold or heat therapy and sauna visits can generate metabolic stress and activate AMPK
  5. Dietary supplements
    Certain supplements can support AMPK, e.g. berberine, alpha lipoic acid and Quercetin. Nicotinamide mononucleotide (NMN) is a chemical that is approved as a dietary supplement in Germany and Europe.
  6. Medications
    Some medications, such as metformin (a diabetes medication) and AICAR (an AMPK activator), can support AMPK activation.

However, it is important to note that any lifestyle changes, such as taking supplements or medications, should always be made in consultation with a doctor. The individual response to these interventions can vary from person to person and is always dependent on various factors such as health status, genetic predisposition, and current medications.

Is mTOR the bad cop? Longevity requires a fine balance.
mTOR, or “mechanistic Target of Rapamycin”, is a key player in our bodies when it comes to cell division and growth. When our body has plenty of energy, mTOR is activated and uses this excess energy to promote muscle and tissue building. An example of the effect of mTOR can be found in people who exercise regularly and consume a lot of animal protein. Through their diet and exercise habits, they increase the activity of mTOR in their bodies, which leads to an increase in muscle mass.

This is particularly important in old age, as maintaining and building muscle mass can protect against sarcopenia, age-related loss of muscle mass, and general frailty. However, as with many things in life, there is a downside. Excessive activity of mTOR can suppress the activity of our longevity genes. From an evolutionary perspective, this makes sense: when there is enough food and therefore energy available, the body focuses on growth and reproduction rather than longevity. In times of abundance, it is more about survival than about the longevity of the individual. It is therefore important to find a balance in mTOR activity to support our health and fitness as well as our longevity.

Plant-based proteins and intermittent fasting: finding the balance with mTOR and reaping its benefits
We all need mTOR to build new cells and maintain our muscle mass. But: excessive mTOR activity has a negative effect on our longevity. An effective way to regulate mTOR activity is to practice moderate calorie restriction or intermittent fasting.

Both strategies can help to temporarily inhibit mTOR and thus maintain balance in the body. It is also important to pay attention to our diet. Animal protein from meat, fish, and dairy products can stimulate mTOR and thus promote cell growth and aging. A healthier alternative is plant-based proteins, which are found in foods such as lentils, beans, and pseudocereals like quinoa. They stimulate mTOR less and should therefore be the preferred main source of protein in our diet.

AMPK, sirtuins and mTOR are the three most important longevity players. On a cellular level, their interaction determines whether or not our body is geared towards longevity. Sirtuins are important longevity switches in our cells. They work together with NAD and help to activate our longevity genes.
AMPK and mTOR are two enzymes in the body that work as antagonists. Studies have shown that increased AMPK activity leads to an increased lifespan and healthspan, promotes autophagy and improves insulin sensitivity. Its counterpart mTOR, on the other hand, is active when there is an energy surplus and uses this to initiate anabolic processes such as muscle building. While mTOR is essential for the body, a sustained increase in mTOR activity is associated with inhibition of longevity genes.

To promote a balance of AMPK and mTOR, moderate calorie restriction, intermittent fasting or the consumption of plant protein instead of animal protein is suitable. Micronutrients such as Quercetin also help to activate the AMPK pathway, inhibit mTOR and boost longevity processes.