Humanity has been striving for longevity not only since Lucas Cranach the Elder's "Fountain of Youth" from 1546, but since its existence. Over time, quacks have turned into scientists, and hidden mysticism has become visible and verifiable facts. With technological evolution, research has gained the necessary tools to approach the complexity of the changes in the human body over time. Science has sometimes consciously, and sometimes only accidentally, been able to identify some dials at the cellular level in experiments.
Communication or information exchange between cells primarily occurs through small molecules and proteins. There are, as with mobile phone signals, one or more sender cells and one or more receiver cells.When the recipient cell registers the signal, chemical messengers transmit the "information" within the cell along specific "paths," leading to a change in the cell's activity. This change in activity can, for example, mean an acceleration or deceleration of work, or it can result in the cell suddenly producing entirely different products.
Four paths to longevity
In relation to aging and longevity, four "paths" have emerged in the molecular playground:
- mTOR
- AMPK
- Sirtuins
- NF-kB
Through the discovery of these four paths, scientists have fundamentally changed our understanding of aging. The representation of these signaling pathways as paths suggests that they are independent routes through the fountain of youth. However, this is a misconception due to the formulation. mTOR, AMPK, sirtuins, and NF-kB are interconnected in various ways and can sometimes influence each other. Nevertheless, for the sake of easier understanding, we want to explore the pathways towards longevity individually. Let's get started.
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 captures and integrates many signals to regulate responses such as cell growth and division, cell death, and inflammation. If the regulation of mTOR does not function properly, it can negatively impact longevity and health.
Both too much activity and too little have proven to be detrimental.In cases of cardiovascular diseases, cancer, obesity, or diabetes, an overactivity of the mTOR pathway was found. A too low mTOR function weakens our immune system. This can also be medically utilized with medications like Rapamycin, which inhibit mTOR. For example, when someone receives a liver transplant, the immune system must be weakened afterwards so that it does not reject the new "foreign" liver.
Additionally, Rapamycin has been the only medication so far that has consistently led to an extension of lifespan 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 the inhibition of mTOR activity led to a reduced occurrence of age-related diseases such as diabetes, cancer, and heart diseases.This interesting approach has already been taken up by research, and possible mTOR-based anti-aging therapies have come closer from afar.
Even independent of possible medications, we can contribute to the balance of signaling pathways. The golden mean of mTOR function can be supported 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 coexistence also holds true on a smaller scale for the cell.A energy metabolism in balance, an improved stress resistance and a qualified household management are all characteristics of an improved health span and a longer lifespan. The AMPK signaling pathway (adenosine monophosphate-activated protein kinase) is involved in regulating all of these properties and can additionally inhibit the previously learned mTOR signaling pathway. As we know, this can have positive effects for us.
AMPK ensures in the body, for example, that glucose from our food is converted into energy and does not accumulate as fat on our hips or bellies. Researchers are taking advantage of this mechanism in diabetes treatment. Metformin is approved as a diabetes medication and acts in the body as an AMPK activator.The medication is certified for its broad effectiveness of AMPK, but it also has a far-reaching impact beyond diabetes. Currently, its potential is 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 a slight inflammation in the body cells. The consequence: we have a higher likelihood of developing diabetes or cardiovascular diseases.
Fortunately, each of us can contribute to longevity through AMPK, so that the functionality of AMPK is better preserved: Intermittent fasting, regular physical training and a possible weight loss.
Did you know?
Not only the diabetes medication Metformin activates the AMPK pathway, but also the naturally occurring Berberine. Berberine increases natural insulin sensitivity and ensures a stable blood sugar level. This makes Berberine an interesting molecule in longevity research, as it can be beneficial against a looming 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 think of this protein family somewhat like politicians. They determine when a project is realized, what it should look like, whether multiple projects run simultaneously, or whether projects are canceled. These decisions are made, at least in theory for politicians, always for the benefit of society, or in the case of sirtuins, for the benefit of the cell and the overall organism.
Due to their important role in relation to the aging process, they are referred to by some as Genes of Longevity . They are involved in cellular metabolism and can regulate many cellular functions, including DNA repair, inflammatory response, cell cycle, or cell death.
Just as a politician needs voters to bring him into a position of decision-making, Sirtuins NAD+ to function. This molecule is present in every cell of the human body and is a significant metabolic regulator. Without NAD+, we would die – NAD+ is that important.
A healthy lifestyle with physical activity, sufficient sleep and fasting episodes can support the integrity of Sirtuin function. Additionally, molecules have been discovered that can increase the NAD+ levels and thus provide fuel for the function of 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 as well. Inflammation is fundamentally a good thing because it helps fend off pathogens and protects us from harmful stimuli. A too low functionality of NF-kB has negative consequences, as our shield is weakened. Overactivation, which is often found in old age, leads to chronic inflammation, the so-called Inflammaging. This trendy term stands for inflammatory aging in German and is one of the Hallmarks of Aging.
When we think of a classic, local inflammation (canker sores in the mouth or joint inflammation), we usually associate it with pain and a limitation of our well-being. In inflammaging, these noticeable signs do not occur. Instead, a subtle inflammation develops in many cells throughout the body, which sustainably damages cell function in general. The therapeutic goal is therefore to slow down the age-related overactivity of NF-kB. A healthy lifestyle with low stress and sufficient rest has also proven to be beneficial.
Quo vadis?
While the chronological age is practically unchangeable, except for forgery, the biological age is different.On one hand, age is an ever-increasing number, while on the biological side, there is predominantly a decrease in the body's adaptability. This decline can now be countered – if one follows the right paths to longevity.
