Humanity has been striving for longevity not just since Lucas Cranach the Elder's “Fountain of Youth” from 1546, but since its existence. Over time, quacks became scientists and hidden mysticism became visible and verifiable facts. With technical evolution, research received the necessary tools to approach the complexity of the changes in the human body over time. Science has sometimes consciously, sometimes just by chance, been able to identify some adjusting wheels at the cell level in experiments.
Communication or the exchange of information between cells essentially takes place via small molecules and proteins. As with cell phone signals, there are one or more transmittercells and one or more receivercells. If the receiving cell registers the signal, chemical messengers pass on the “information” within the cell along special “paths” and thereby lead to a change in the cell’s activity. This change in activity can, for example, mean an acceleration or slowing down of work, but it can also lead to the cell suddenly producing completely different products.
Four paths to longevity
With regard to aging and longevity, four “pathways” have emerged on the molecular playground:
- mTOR
- AMPK
- Sirtuins
- NF-kB
By discovering these four pathways, scientists have succeeded in fundamentally changing our understanding of aging. The representation of these signal paths as paths suggests that they are independent marching routes through the fountain of youth. However, this is an error due to the wording. mTOR, AMPK, sirtuins and NF-kB are connected to each other in many ways and sometimes depend on each other. Nevertheless, for reasons of easier understanding, we want to take the paths towards longevity one at a time. Let's get going.
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 of it proved detrimental. Hyperfunction of the mTOR pathway was found in cardiovascular diseases, cancer, obesity or diabetes. Too low mTOR function weakens our immune system. This can also be used medically with drugs such as rapamycin, which inhibit mTOR. For example, if someone receives a liver transplant, their 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 life extension in studies on mice. However, these were kept in a germ-free environment and therefore did not rely on a strong immune system. Nevertheless, the results are encouraging, as age-related diseases such as diabetes, cancer and heart disease were reduced by inhibiting mTOR activity. Research has already taken up this interesting approach and possible anti-aging therapies based on mTOR have moved from a distance to close proximity.
We can also contribute to the signaling pathway balance independently of possible medications. The golden mean of mTOR function can be achieved by:
- a healthy lifestyle with enough exercise,
- occasional fasting episodes
- and the reduction of animal proteins in our meals.
AMPK – metformin, free radicals and mTOR inhibition
What applies to coexistence also applies on a smaller scale to the cell. A energy metabolism in balance, improved stress resistance and skilled housekeeping are all characteristics of improved healthspan and extended lifespan. The AMPK signaling pathway (Adenosine monophosphate-activated protein kinase) is involved in the regulation of all of these properties and can also inhibit the previously known 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 in the form of fat on our hips or stomachs. Researchers use this mechanism in diabetes treatment. Metformin is approved as a diabetes medication and acts as an AMPK activator in the body. The drug is said to have broad effectiveness of AMPK, but its appeal goes far beyond diabetes. The potential for this is currently being examined in several studies.
We know from various research efforts 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 cause metabolic disorders and slight inflammation in the body's cells. The result: we have a higher probability of developing diabetes or cardiovascular disease.
Fortunately, each of us can contribute to longevity through AMPK to better maintain the functionality of AMPK: Intermittent fasting, regular physical training and possible 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 consistent blood sugar levels. This makes berberine an interesting molecule in longevity research, as it can be useful, among other things, against impending insulin resistance .
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 protein family somewhat like politicians. These determine when a project is implemented, what it should look like, whether several projects run at the same time or whether projects are canceled. For politicians, at least in theory, these decisions are always made for the good of society or in the case of sirtuins, for the benefit of the cell and the entire organism.
Because of their important role in the aging process, they are sometimes referred to as longevity genes. They are involved in cellular metabolism and can regulate many cellular functions, including DNA repair, inflammatory response, cell cycle or cell death.
However, just as a politician needs voters to put him in the position of decision-making, 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 the NAD+ level and thus form fuel for the function of the sirtuins.
NF-kB – Inflammaging
Nuclear factor kappa-B (NF-kB) is involved in the regulation of inflammatory processes. Similar to mTOR, the dose makes the poison here too. Inflammation is fundamentally a good thing because it helps ward off pathogens and protects us from harmful stimuli. If the functionality of NF-kB is too low, this has negative consequences because our protective shield is weakened. Overactivation, as is often found in old age, leads to chronic inflammation, the so-called Inflammaging. This hip term stands for inflammatory aging in German and is one of the Hallmarks of Aging.
When we think of classic, local inflammation (mouth ulcers or joint inflammation), we usually associate it with pain and a reduction in our well-being. These noticeable signs do not occur with inflammation. Instead, underlying inflammation develops in many cells throughout the body, causing lasting damage to cell function in general. The therapeutic goal is therefore to slow down the age-related overfunction 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 same is true with the biological age different. On the one hand, age is an ever-increasing number, while on the biological side it is mostly a decline in the body's ability to adapt. This decline can now be countered - if you follow the right paths to longevity.
