Longevity research has identified three important signaling pathways in our body that are largely responsible for slowing down the ageing process in the body and promoting health. They act as energy and nutrient sensors in the body and react to changes in the cell. Each player has its own mechanism that regulates bodily functions and the ageing process. All three pathways work together in synergy and are essential for the body. However, they have different effects on the processes that influence our longevity and on different metabolic pathways.
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 must first consider how our DNA is packaged in cells.
Imagine our DNA as an incredibly long string – if the DNA of all the cells in our body were strung 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 the DNA onto tiny “coils” called histones. The DNA packaged in this way is then neatly stowed away in the cells.
NAD – without this coenzyme, sirtuins are powerless
Now 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 referred to as “epigenetic regulators”.
However, in order to operate these switches and activate our longevity genes, the sirtuins require a special coenzyme called NAD (nicotinamide adenine dinucleotide). However, as we age, the amount of available NAD in our body decreases. Without this essential cofactor, the sirtuins can no longer work effectively and their activity decreases. This is thought to be one of the reasons why we become more susceptible to disease as we age.
AMPK – the energy conductor of the cell
Finally, adenosine monophosphate-activated protein kinase 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 to obtain energy from fats and it promotes autophagy, a process in which the 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 AMPK not being sufficiently activated. AMPK is activated by muscle contractions during exercise, but AMPK activity may be reduced in people who do little or no exercise.
Unhealthy diet:
An unbalanced diet with an excess of calories, especially carbohydrates and fats, can impair the activation of AMPK. A 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 with AMPK activation. Insulin resistance can disrupt the AMPK signaling pathway, resulting in reduced AMPK activity. Obesity can also impair the function of AMPK in adipose tissue.
Ageing process:
AMPK activity tends to decrease with age. This may contribute to older people having difficulty activating AMPK effectively, which can have an impact on metabolism and energy homeostasis. This means the balance between energy input and output that the body needs for optimal performance.
Genetic factors:
Individual genetic predisposition can also play a role. Some people have genetic variations that can affect AMPK function.
Chronic stress:
Chronic stress can affect the energy balance and inhibit AMPK activation. Stress hormones can influence the AMPK signaling pathways and thus disrupt normal activation. Insufficient activation of AMPK accelerates the ageing process and can shorten the lifespan and especially the health span. The diabetes drug metformin and the natural plant substance quercetin activate the AMPK signaling pathway in the body and improve insulin sensitivity.
How you can activate AMPK
Activation of AMPK (adenosine monophosphate-activated protein kinase) can occur in a number of ways, including through lifestyle changes, diet, exercise and certain medications. Here are some strategies to activate AMPK:
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 also activate AMPK, especially in the muscles.
Calorie restriction and intermittent fasting:
Reduced calorie intake and intermittent fasting can activate the AMPK signaling pathway as they lead to an increase in AMP relative to ATP.
Healthy nutrition:
- Low-fat, high-fiber diet: A diet low in saturated fatty acids and rich in fiber can support AMPK activation.
- Foods that promote AMPK: Foods such as green tea, curcumin (in turmeric), resveratrol( in red grapes) and omega-3 fatty acids( in fish) can activate AMPK.
Metabolic stressors:
Cold or heat therapy and sauna visits can generate metabolic stress and activate AMPK.
Food supplements:
Certain dietary supplements can support AMPK, e.g. berberine, alpha-lipoic acid and quercetin.
Medication:
Some medications, such as metformin (a diabetes medication) and AICAR (an AMPK activator), can support AMPK activation.
Food supplements that are approved in the UK:
Nicotinamide mononucleotide( NMN) is a chemical that is approved as a dietary supplement in the United Kingdom. According to German and European law, NMN (nicotinamide mononucleotide) is a chemical that is not suitable for human consumption. The use of NMN is your sole responsibility. Keep out of the reach of children and adolescents. For scientific, research and laboratory use only.
However, it is important to mention in this context that any lifestyle changes, such as the intake of dietary supplements or medication, 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 state of health, genetic predisposition and current medication.
Is mTOR the bad cop? Longevity requires a fine balance
mTOR, or “Molecular Target of Rapamycin”, is a key player in our body when it comes to cell division and growth. At times when our body has plenty of energy, mTOR is activated. It uses this excess energy to promote muscle and tissue growth. 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. This causes them to build up more muscle mass.
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. But as with so many things in life, there is a downside. Too much mTOR activity can inhibit the activity of our longevity genes. From an evolutionary perspective, this makes sense: when there is enough food and therefore energy, the body focuses on growth and reproduction rather than longevity. In times of abundance, it is therefore more about the survival of the species than about individual longevity. 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
The fact is, we all need mTOR to build new cells and maintain our muscle mass, but too much mTOR is counterproductive to our longevity. One way to regulate mTOR activity is through 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 what we eat. Animal protein from meat, fish and dairy products can stimulate mTOR and thus promote cell growth and ageing. Plant proteins are a healthier alternative. These can be found in foods such as lentils, beans, soy or pseudocereals such as quinoa. They stimulate mTOR less strongly and should therefore be the preferred main source of protein in our diet.
Conclusion
Situine, AMPK and mTOR are the three most important players in longevity. At the cellular level, their interaction determines whether our body is geared towards longevity or not. 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. Although mTOR is essential for the body, a permanent increase in mTOR activity is associated with an inhibition of longevity genes.
To promote a balance of AMPK and mTOR, moderate calorie restriction, intermittent fasting or the consumption of plant rather than animal protein are suitable. Nutrients such as quercetin also help to activate the AMPK pathway, inhibit mTOR and boost longevity processes.
Sources:
- Yanjun Li, Yingyu Chen. AMPK and autophagy. Adv Exp Med Biol. 2019.
- Hannah R Spaulding, Zhen Yan. AMPK and the Adaptation to Exercise. Annu Rev Physiol. 2022.
- Marc Foretz et al. Metformin: from mechanisms of action to therapies. Cell Metab. 2014.
- Fengwei Zhang et al. Quercetin modulates AMPK/SIRT1/NF-κB signaling to inhibit inflammatory/oxidative stress responses in diabetic high fat diet-induced atherosclerosis in the rat carotid artery. Exp Ther Med. 2020.
- Enyu Rao et al. AMPK-dependent and independent effects of AICAR and compound C on T-cell responses. Oncotarget. 2016.
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