In this text about the deregulated nutrient measurement As the fifth hallmark of aging, we need to delve a little deeper into the biochemistry of the cell. Don't worry, it sounds worse than you think, but to better understand the Hallmarks of Aging, we need a few technical terms, such as mTOR, sirtuins, IGF-1 or AMPK. You can find out more in our article about the four longevity pathways.
But even without this article, you will know at the end of this article, why calorie restriction has led to longer lives in so many animalsThe fact that certain forms of fasting and caloric restriction have far-reaching significance for the general public is demonstrated by the Nobel Prize for Physiology and Medicine awarded in 2016. Yoshinori Ohsumi, a Japanese cell biologist, received the prestigious award for his achievements in the advanced understanding of autophagy.
This is a process in which damaged cell components are broken down when cells are "starved" for a certain period of timeThis allows aged cells to regain their functionality – a kind of recycling program.
Fast but means more than autophagy. When it comes to the connection between fasting and longevity, there is a lot hidden in the depths of molecularity. We'll go deep with you and uncover the molecular pathways behind fasting.
Fasting inhibits the IGF-1 signaling pathway and mTOR. Fasting induces AMPK and sirtuins and thereby combats aging.
Hormones and their axes
There are countless hormones in the body that control processes such as muscle growth, menstruation or digestion. However, hormones usually do not exert their effect directly. They are very often organized along so-called axes or pathways, which means that one hormone stimulates another hormone and so on until the final organ where a hormone then exerts its effect.
So that you don't have to study an entire lecture on the topic, we will focus on one hormone axis that has to do with longevity research.
Did you know? If our body produces too much of the growth hormone GH in adulthood, it can lead to the disease acromegaly The hands and face are usually affected first and become unnaturally large. The cause is usually an autonomous overproduction of GH in the pituitary gland.
The somatotropic axis: GH and IGF-1
The somatotropic axis includes the growth hormone (GH, from English growth hormone) which is produced by the pituitary gland and the insulin-like growth factor (IGF-1, insulin-like growth factor). As part of this axis, GH is released by the pituitary gland, which in turn stimulates cells (especially liver cells) to produce IGF-1.
The signaling within the cell by IGF-1 is the same as that triggered by insulin, which informs the cells about the presence of glucose (sugar) – hence IGF-1 has its characteristic name. So when we eat something, the blood sugar and thus also IGF-1 and insulin.
The diagram shows you the two main effects of IGF-1 that are of interest to us. On the one hand, the transcription factors of the FOXO family are inhibited and on the other hand, mTOR is activated.
Before we confuse you with more complicated names, let me give you a brief explanation. FOXO stands for Forkhead box Class O and in this form for a series of transcription factors. Such molecules can switch certain parts of our DNA on or off. You can find out more about this in the article about epigenetic changes.
The name mTOR stands for mammalian target of rapamycin. It owes its name to the discovery that the drug rapamycin binds to this receptor. More on this later. Both signaling pathways are involved in aging and have been conserved through evolution because they have provided a survival advantage.
Excursus: Evolutionary Conservation
Evolutionary preservation has nothing to do with the preservation of food, but its meaning is similar to the term we know. More precisely: In evolution, there is constant selection pressure and only the most functional organisms survive.
When certain genetic sequences or signaling pathways occur over millions of years, it means that one organism gains a selective advantage and the others become extinct. Nowadays, this selection pressure is somewhat overridden by the highly developed medical possibilitiesIn the Stone Age, anyone who had a heart attack was almost certain to die – today we have intensive care medicine and a range of medications that prevent this.
Studies have now made some interesting findings in this regard. Small genetic mutations that reduce the function of IGF-1 have been linked to longevity in both humans and model organismsThis is remarkable and also shows the importance of such paths for a long and healthy life.
IGF-1 signaling pathway
The following result has been replicated time and again in numerous studies: Attenuation of the IGF-1 signaling pathway consistently extends lifespan of flies, worms and mice, for example. This has to do with the transcription factor FOXO which has also been widely studied. Under normal circumstances, IGF-1 inhibits the FOXO family and the transcription factors cannot therefore exert their effect. If the IGF-1 signaling pathway is inhibited, then FOXO can work and ensure that proteins are produced from the DNA that counteract the aging process.
The Paradox
However, it would be too simple if that were all. As we grow older, we would expect, based on the above findings, that we find a high IGF-1 level, as this signaling pathway is, among other things, the cause of aging. This is exactly where the crux of the matter comes.
Some other studies described that during the normal aging process GH and IGF-1 levels sink. In mice with accelerated aging, the concentration also decreased. So we have to abandon our theory about aging and higher IGF-1 levels?
Not according to the proponents of the following theory. According to this theory, organisms with lower IGF-1 functionality can survive longer in old age because this leads to slower cell growth and a more leisurely metabolism. This ultimately means less cell damage, which in turn is good for us.
The body helps itself again by simply downregulating the signaling pathway with age in order to minimize damageAs is often the case, our body's ability to balance is called for, because extremely low IGF-1 levels are not compatible with life. This is quite logical when you remember the influence of IGF-1 on metabolism and cell growth. The different study results no longer exclude each other, but complement each other.
Did you know? A varied and plant-rich diet contributes significantly to our healthy aging. The signaling pathways that can be activated by food are diverse. One of them is the IGF-1 pathway. The IGF-1 contained in broccoli sulforaphane was able to extend the life of C.elegans in a study on the induction of lower IGF-1 levels.
mTOR, AMPK, Sirtuins and Fasting
In addition to the IGF-1 signaling pathway, which is known to be involved in glucose sensing, three other related and interconnected nutrient sensing systems are in focus:
- mTOR is used to record high amino acid concentrations – rises after a protein-rich meal.
- AMPK recognizes low energy states through high AMP levels. AMP is produced when the body's most important energy source, ATP, is consumed.
- sirtuins, also known as longevity genes, detect low energy states by perceiving high NAD-Reflect.
Becomes mTOR downregulated, yeast, worms and flies live longer. Drugs can specifically target mTOR with the active ingredient Rapamycin This mechanism of action is used in transplant surgery. After kidney transplants, rapamycin is an important suppressor of the immune system so that the foreign kidney is not immediately rejected by the body.
As promising as the studies on mTOR inhibition and lifespan are, the side effects of long-term rapamycin treatment are so worrying. Poor wound healing, insulin resistance and cataracts say hello here.
Nevertheless, Rapamycin is the most robust chemical intervention ever discovered to extend lifespan in mammals.It is therefore all the more important to understand the mechanisms involved in order to determine the extent to which harmful and beneficial effects of mTOR inhibition can be separated
Did you know? The American doctor and longevity expert Peter Attia dedicates an entire chapter to rapamycin in his successful book "Outlive". The first studies are promising, but since rapamycin has very strong side effects and is prescription-only, you should definitely not experiment with it.
Another method to keep mTOR levels low is fasting. But so-called fasting mimetics (molecules that trick the body into thinking it is in a fasting situation) can also keep mTOR levels low. These include, among others, berberine.
Of Nutrient Abundance and Nutrient Scarcity
mTOR, like IGF-1, must be downregulated to produce positive effects on aging. While IGF-1 (presence of glucose) and mTOR (presence of amino acids) signal nutrient richness, AMPK and sirtuins report nutrient shortages (absence of energy). Consequently, a stronger effect of AMPK and sirtuins promotes healthy aging.
The AMPK level is increased by metformin, for example. The drug is one of the oldest and best researched diabetes medications. In worms and mice without a history of diabetes, the administration of metformin extended lifespan.
Did you know? Green tea has been considered healthy for centuries and scientists have now identified the active ingredients behind it. The theanine a calming effect and can be just like EGCG have a positive effect on blood sugar metabolism.
Gandhi, Fasting and the Future
Overall, the currently available scientific information supports the idea that that the regulation of nutrient absorption contributes to a longer healthy lifeIn addition, the research results based on the active ingredients rapamycin and metformin are as impressive as they are promising.
Although much detailed research is still pending, from the current perspective it can be said that that our fifth hallmark of aging is also a promising starting point for influencing aging – and that is already happening now. After all, the positive effects of fasting are already evident and understandable at this point in time.
Mahatma Gandhi once said:
“Fasting is part of my being. I can no more do without it than I can do without my eyes. What the eyes are to the external world, fasting is to the internal world.”
What was spiritual then is today biochemical reality… at least the second part.
The next article in this series is about the sixth hallmark of aging: mitochondrial dysfunction.
MoleQlar ONE combines 13 qualified longevity molecules and a harmonious lemon flavor. Together, the ingredients cover all molecular signs of aging.
