The Three Key Players in Longevity: Sirtuins, AMPK and mTOR

Longevity research has identified three important signalling pathways in our body that play a key role in slowing ageing processes and promoting health. They act as energy and nutrient sensors in the body and respond to changes within the cell. Each player has its own mechanism for regulating bodily functions and the ageing process. All three pathways work together synergistically and are essential for the body. Nevertheless, they have different effects on the processes that influence our longevity and on various metabolic pathways.

Table of contents

1. Sirtuins – the switches of longevity
2. NAD – without this coenzyme, sirtuins are powerless
3. AMPK – the cell’s energy conductor
4. AMPK and health: its key role in metabolism
5. How to activate AMPK
6. Is mTOR the bad cop? Longevity requires a fine balance
7. Plant proteins and intermittent fasting: finding balance with mTOR
8. Conclusion
9. Sources

Sirtuins – the switches of longevity

Sirtuins are special proteins in our body that play an important role in controlling our genes. To understand how they do this, we first need to consider how our DNA is packaged inside cells.

Imagine our DNA as an incredibly long string – if the DNA from all the cells in our body were laid end to end, it would cover the distance from the Earth to the sun a thousand times over. This enormous length ultimately has to fit inside our tiny cells. To make this possible, the body winds the DNA around tiny “spools” called histones. The packaged DNA is then neatly stored inside the cells.

NAD – without this coenzyme, sirtuins are powerless

This is where sirtuins come into play. They have the ability to modify 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 referred to as “epigenetic regulators”.

However, to operate these switches and activate our longevity genes, sirtuins require a special coenzyme called NAD (nicotinamide adenine dinucleotide). As we age, however, the amount of NAD available in the body declines. Without this essential cofactor, sirtuins can no longer work effectively and their activity decreases. This is believed to be one reason why we become more susceptible to disease as we grow older.

AMPK – the cell’s energy conductor

Adenosine monophosphate-activated protein kinase also plays an important role. AMPK is an enzyme in our cells that influences insulin sensitivity and glucose uptake. It acts like a guardian that constantly checks whether our cells have sufficient energy. When energy becomes scarce, AMPK is activated and ensures that more energy is made available.

At the same time, AMPK inhibits its counterpart mTOR (“mechanistic Target of Rapamycin”), which regulates energy-consuming growth processes in our cells. When mTOR is too active, cells use more energy to drive anabolic processes. AMPK therefore ensures that our cells use energy efficiently during periods of food scarcity. But AMPK does even more: it helps cells generate energy from fats and promotes autophagy, a process through which cells cleanse and rejuvenate themselves. You can read more about how these signalling pathways interact with a specific plant compound in our article Resveratrol and longevity.

AMPK and health: its key role in metabolism

AMPK activation can be influenced by various factors, and there are several reasons why many people find it difficult to activate AMPK effectively:

• Sedentary lifestyle and lack of physical activity: An inactive lifestyle and insufficient physical activity can result in inadequate AMPK activation. AMPK is activated by muscle contractions during exercise, but in people who exercise little or not at all, AMPK activity may be reduced.
• Unhealthy diet: An unbalanced diet with excess calories, particularly from carbohydrates and fats, can impair AMPK activation. A high calorie intake, especially from poor-quality sources, can increase ATP levels and hinder AMPK activation.
• Insulin resistance and obesity: People with insulin resistance or obesity often experience problems with AMPK activation. Insulin resistance can disrupt the AMPK signalling pathway, resulting in reduced AMPK activity. Obesity can also impair AMPK function in adipose tissue.
• Ageing process: AMPK activity tends to decline with age. This may contribute to older people finding it more difficult to activate AMPK effectively, which can affect metabolism and energy homeostasis. This refers to the balance between energy intake and energy expenditure that the body requires for optimal performance.
• Genetic factors: Individual genetic predisposition may also play a role. Some people have genetic variations that can affect AMPK function.
• Chronic stress: Chronic stress can disrupt energy balance and inhibit AMPK activation. Stress hormones can influence AMPK signalling pathways and thereby interfere with normal activation. Insufficient AMPK activation accelerates the ageing process and may shorten lifespan and, in particular, healthspan. The diabetes medication metformin and the natural plant compound quercetin activate the AMPK pathway in the body and improve insulin sensitivity.

You can find approaches to targeted stress reduction that may also benefit metabolism in our article Reducing stress with nutrition, meditation and vital nutrients.

How to activate AMPK

AMPK (adenosine monophosphate-activated protein kinase) can be activated in various ways, including through lifestyle changes, diet, exercise and certain medications. Here are some strategies for activating AMPK:

Regular physical activity

• Aerobic exercise: Endurance activities such as running, cycling and swimming can activate AMPK because they influence ATP and AMP levels.
• Resistance training: Strength training can also activate AMPK, particularly in the muscles.

Calorie restriction and intermittent fasting

Reduced calorie intake and intermittent fasting can activate the AMPK pathway because they increase AMP relative to ATP.

Healthy diet

• Low-fat, high-fibre diet: A diet low in saturated fatty acids and rich in fibre can support AMPK activation.
• Foods that promote AMPK: Foods such as green tea, curcumin from turmeric, resveratrol from red grapes and omega-3 fatty acids from fish may activate AMPK.

Metabolic stressors

Cold or heat therapy and sauna sessions can create metabolic stress and activate AMPK.

Food supplements

Certain food supplements may support AMPK, including berberine, alpha-lipoic acid and quercetin.

Medications

Some medications, such as metformin, a diabetes medication, and AICAR, an AMPK activator, can support AMPK activation.

Food supplements authorised in the UK

Nicotinamide mononucleotide (NMN) is a chemical authorised as a food supplement in the United Kingdom. Under German and European law, NMN (nicotinamide mononucleotide) is classified as a chemical that is not suitable for human consumption. The use of NMN is entirely at your own risk. Keep out of the reach of children and adolescents. For scientific, research and laboratory use only.

Good to know: Any lifestyle change, including taking food supplements or medications, should always be discussed with a doctor. Individual responses to these interventions can vary from person to person and depend on health status, genetic predisposition and current medication.

Is mTOR the bad cop? Longevity requires a fine balance

mTOR, or “mechanistic Target of Rapamycin”, is a key player in our body when it comes to cell division and growth. When the body has plenty of energy available, mTOR is activated. It uses this excess energy to promote the growth of muscle and tissue. One example of mTOR’s effects can be seen in people who regularly engage in strength training and consume large amounts of animal protein. Their dietary and exercise habits increase mTOR activity in the body, which leads to greater muscle growth.

This is particularly important in old age, as maintaining and building muscle mass can protect against sarcopenia, the age-related loss of muscle mass, and general frailty. However, as with many things in life, there is also a downside: excessively high mTOR activity can inhibit the activity of our longevity genes. From an evolutionary perspective, this makes sense. When sufficient food and energy are available, the body focuses on growth and reproduction rather than longevity. In times of abundance, the priority is therefore the survival of the species rather than the long life of the individual. It is consequently important to find a balance in mTOR activity in order to support both health and fitness as well as longevity. We explore how this signalling pathway relates to metabolism as a whole in our article Longevity and mTOR.

Plant proteins and intermittent fasting: finding balance with mTOR and making use of its benefits

The fact is that we all need mTOR to form new cells and maintain muscle mass, but too much mTOR is counterproductive for longevity. One way to regulate mTOR activity is through moderate calorie restriction or intermittent fasting.

Both strategies can help inhibit mTOR temporarily and maintain balance in the body. It is also important to pay attention to the foods we consume. Animal protein from meat, fish and dairy products can stimulate mTOR and thereby promote cell growth and ageing. A healthier alternative is plant-based protein. This is found in foods such as lentils, beans, soy and pseudocereals such as quinoa. These foods stimulate mTOR less strongly and should therefore be preferred as the primary source of protein in our diet. Our article Longevity and metabolism explains how these relationships fit into the broader context of metabolism.

Conclusion

Sirtuins, AMPK and mTOR are the three most important players in longevity. At the cellular level, their interaction determines whether the body is oriented towards longevity or not. Sirtuins are important longevity switches in our cells. They work together with NAD and help activate longevity genes. AMPK and mTOR are two enzymes in the body that act as opposing forces.

Key finding: Increased AMPK activity promotes lifespan and healthspan, stimulates autophagy and improves insulin sensitivity. Its counterpart mTOR is active when there is an energy surplus and uses this to initiate anabolic processes such as muscle growth. However, permanently elevated mTOR activity is associated with the inhibition of longevity genes.

Moderate calorie restriction, intermittent fasting and replacing animal protein with plant protein can help promote a healthy balance between AMPK and mTOR. Nutrients such as quercetin may also help activate the AMPK pathway, inhibit mTOR and stimulate longevity-related processes.

Sources

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