Mankind has been striving for longevity not just since Lucas Cranach the Elder's "Fountain of Youth" in 1546, but since its very existence. Over time, quacks became scientists and hidden mysticism became visible and verifiable facts. Technological evolution gave research the tools it needed to approach the complexity of changes in the human body over time. Science has sometimes consciously, sometimes only by chance, been able to identify a few adjusting wheels at the cellular level in experiments.
Communication and the exchange of information between cells essentially takes place via small molecules and proteins. As with cell phone signals, there are one or more sendercells and one or more receivercells. When the recipient cell registers the signal, chemical messengers transmit the "information" within the cell along special "pathways", leading to a change in the cell's activity. This change in activity can mean, for example, an acceleration or deceleration of work, but it can also lead to the cell suddenly producing completely different products.
On four paths to longevity
With regard to aging and longevity, four "pathways" have emerged on the molecular playground:
- mTOR
- AMPK
- Sirtuine
- NF-kB
The discovery of these four pathways has enabled scientists to fundamentally change our understanding of ageing. The presentation of these signaling pathways as pathways suggests that they are independent routes through the fountain of youth. However, this is a misconception due to the wording. mTOR, AMPK, sirtuins and NF-kB are interconnected in many ways and are sometimes mutually dependent. Nevertheless, we want to take the paths towards longevity one by one for the sake of clarity. Let's get on our way.
mTOR - rapamycin, mice and fasting
mTOR (mechanistic target of rapamycin) is a protein found in all mammals, including humans, that functions as a signaling hub in the cell. This means that mTOR senses and integrates many signals to control responses such as cell growth and division, cell death and inflammation. If the regulation of mTOR does not work, this can have a negative impact on longevity and health.
Both too much activity and too little activity have been shown to be detrimental. Hyperfunction of the mTOR pathway was found in cardiovascular disease, cancer, obesity and diabetes. Too little mTOR function weakens our immune system. This can also be exploited medically with drugs such as rapamycin, which inhibit mTOR. For example, if someone receives a liver transplant, the immune system must be weakened so that it does not reject the new "foreign" liver.
In addition, rapamycin is the only drug to date that has consistently led to a prolongation of life in studies on mice. However, these were kept in a germ-free environment and were therefore not dependent on a strong immune system. Nevertheless, the results are encouraging, as the inhibition of mTOR activity reduced the incidence of age-related diseases such as diabetes, cancer and heart disease. This interesting approach has already been taken up by researchers and potential anti-ageing therapies based on mTOR have thus moved from afar into the near future.
We can also make a contribution to signaling pathway balance independently of potential drugs. The golden mean of the mTOR function can be defined by:
- a healthy lifestyle with sufficient exercise,
- occasional fasting episodes
- and the reduction of animal proteins in our meals
AMPK - metformin, free radicals and mTOR inhibition
What applies to living together also applies on a smaller scale to the cell. An energy metabolism in balance, improved resistance to stress and skilled housekeeping are all hallmarks of improved healthspan and prolonged lifespan. The AMPK (adenosine monophosphate-activated protein kinase) signaling pathway is involved in regulating all of these traits and can additionally inhibit the previously learned mTOR signaling pathway. As we know, this can have positive effects for us.
AMPK, for example, ensures that the glucose from our food is converted into energy in the body and does not end up as fat on our hips or stomachs. Researchers are making use of this mechanism in the treatment of diabetes. Metformin is approved as a diabetes drug and acts as an AMPK activator in the body. However, due to the broad effectiveness of AMPK, the drug is said to have potential far beyond diabetes. Its potential is currently being investigated in several studies.
From various research efforts, we know that the responsiveness of AMPK decreases with age - unfortunately. This loss impairs metabolic regulation and increases the number of free radicals in the body. These age-related changes then lead to metabolic disorders and mild inflammation in the body's cells. As a result, we are more likely to develop diabetes or cardiovascular disease.
Luckily, each of us can contribute to longevity via AMPK to better maintain AMPK functionality: intermittent fasting, regular physical exercise and eventual weight loss.
Did you know
Not only the diabetes drug metformin activates the AMPK pathway, but also the naturally occurring berberine. Berberine increases natural insulin sensitivity and ensures a steady blood sugar level. This makes berberine an interesting molecule in longevity research, as it can be useful against impending insulin resistance , among other things.
Sirtuins - genes of longevity and NAD+
Sirtuins is a collective term for a family of seven proteins (SIRT 1 - SIRT 7). We can imagine this family of proteins as being similar to politicians. They decide when a project should be realized, what it should look like, whether several projects should run simultaneously or whether projects should be abandoned. In the case of politicians, at least in theory, these decisions are always made for the good of society or, in the case of sirtuins, for the good of the cell and the organism as a whole.
Because of their important role in the ageing process, they are sometimes referred to as longevity genes . They are involved in cell metabolism and can regulate many cell functions, including DNA repair, inflammatory response, cell cycle or cell death.
However, just as a politician needs voters to put him in a position to make decisions, sirtuins need NAD+ to function. This molecule is found in every cell of the human body and is an important metabolic regulator. Without NAD+ we would die - that's how important NAD+ is.
A healthy lifestyle with physical activity, sufficient sleep and fasting episodes can support the integrity of sirtuin function. In addition, molecules have been discovered that can increase NAD+ levels and thus provide fuel for sirtuin function.
NF-kB - Inflammaging
Nuclear Factor kappa-B (NF-kB) is involved in the regulation of inflammatory processes. As with mTOR, the dose makes the poison. Inflammation is basically a good thing because it helps us to fight off pathogens and protect us from harmful stimuli. If the functionality of NF-kB is too low, this has negative consequences because our protective shield is weakened. Overactivation, which is often found in old age, leads to chronic inflammation, known as inflammaging. This hip term stands for inflammatory ageing and is one of the hallmarks of ageing.
When we think of a classic, localized inflammation (mouth ulcers or joint inflammation), we usually associate it with pain and a reduction in our well-being. These tangible signs do not occur with inflammaging. Instead, a subliminal inflammation develops in many cells throughout the body, which generally causes lasting damage to cell function. The therapeutic goal is therefore to slow down the age-related hyperfunction of NF-kB. A healthy lifestyle with little stress and sufficient rest has also proven to be beneficial
Quo vadis?
While the chronological age is practically unchangeable, with the exception of document forgery, the biological age is different. On the one hand, age is an ever-increasing number; on the biological side, it is mostly a decrease in the body's ability to adapt. This decline can now be countered - if the right paths are taken towards longevity.
