In this text about 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 thought, but to better understand the Hallmarks of Aging, we need a few technical terms, like mTOR, Sirtuine, IGF-1 or AMPK. You can find out more about this in our article about the four longevity paths.
But even without this article, at the end of this article you will know why calorie restriction has led to longer lives in so many animals. The Nobel Prize for Physiology and Medicine, awarded in 2016, shows that certain forms of fasting and caloric restriction have far-reaching significance for the general public. Yoshinori Ohsumi, a Japanese cell biologist, received the prestigious award for his achievements in expanding our understanding of autophagy.
This is a process in which damaged cell components are broken down when cells “starve” for a certain period of time. As a result, aged cells regain their functionality - a kind of recycling program.
Fasting but means more than autophagy. When it comes to the question of the connection between fasting and longevity, a lot lies hidden in the depths of molecularity. We'll go deeper 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 fights 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 have their effect directly. They are very often along so-called axes or Organized in pathways, which means that one hormone stimulates another hormone and so on up to the end organ, where a hormone then develops its effect.
So that you don't have to study an entire lecture on the topic, we'll focus on a 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 clinical picture of Acromegaly come. 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, from engl. insulin-like growth factor). As part of this axis, GH is now released by the pituitary gland and this in turn stimulates cells (especially liver cells) to produce IGF-1.
The signal transmission within the cell of 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 with it IGF-1 and insulin inevitably rise.
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's give you a quick explanation. FOXO stands for Forkhead box Class O and in this form it stands for a number 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 gets its name from the discovery that the drug rapamycin binds to this receptor. Later more. Both signaling pathways are involved in aging and have been conserved through evolution as they have conferred a survival advantage.
Excursus: Evolutionary Conservation
Evolutionary preservation has nothing to do with the preservation of food, but the meaning of the word is similar to the term we are familiar with. More precisely: In evolution there is constant selection pressure and only the most functional organisms survive.
If certain genetic sequences or signaling pathways occur over millions of years, this means that one organism receives a selection advantage and the others die out. Today, this selection pressure is somewhat overridden by the highly developed medical possibilities. Anyone who had a heart attack in the Stone Age almost certainly died - today there is intensive care medicine and a number of medications that prevent this.
Studies have now made some interesting findings in this context. Small genetic mutations that reduce the function of IGF-1 have been associated with longevity in both humans and model organisms. This 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 again and again in numerous studies: A weakening of the IGF-1 signaling pathway consistently extends the lifespan of, for example, flies, worms and also mice . This has, among other things, 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 are therefore unable to exert their effect. If the IGF-1 signaling pathway is now 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 easy if that was all. As we get older, then based on the above findings we would expect that we would find a high IGF-1 level, since this signaling pathway is, among other things, the cause of aging. This is exactly where the crux comes.
Some other studies have described that GH and IGF-1 levels decrease during the normal aging process. The concentration also decreased in mice with accelerated aging. So we probably have to reject our theory about aging and higher IGF-1 levels?
Not according to representatives of the following theory. Accordingly, organisms with lower IGF-1 functionality can survive longer in old age because this leads to slower cell growth and a slower 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 keep damage to a minimum. As is so often the case, our body's balancing abilities are also in demand, because extremely low IGF-1 levels are not compatible with life. This is quite logical if you remember the influence of IGF-1 on metabolism and cell growth. The different study results are no longer mutually exclusive, but rather complement each other.
Did you know? A varied and plant-rich diet makes a significant contribution to ensuring that we age healthily. The signaling pathways that can be activated by food are diverse. One of these is the IGF-1 pathway. The sulforaphane contained in broccoli was able to save the life of C. in a study on the induction of lower IGF-1 levels.extend elegans.
mTOR, AMPK, sirtuins and fasting
In addition to the IGF-1 signaling pathway, which is known to be involved in glucose measurement, the focus is on three other related and interconnected nutrient sensing systems:
- mTOR is used to detect high amino acid concentrations - increases after a protein-rich meal.
- AMPK detects low energy states due to high AMP levels. AMP is created when the body's most important energy source, ATP, is consumed.
- Sirtuins, also called longevity genes, detect low energy states by sensing high NAD mirroring.
If mTOR is downregulated, yeast, worms and flies live longer. mTOR can be inhibited in a targeted manner using 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 just as worrying. Poor wound healing, insulin resistance and cataracts send their regards.
Nevertheless, rapamycin is the most robust chemical intervention ever discovered to extend lifespan in mammals. It is all the more important to understand the mechanisms involved in order to determine to what extent harmful and beneficial effects of mTOR inhibition can be separated
Did you know? The American doctor and longevity expert Peter Attia dedicates his successful Book “Outlive” Rapamycin an entire chapter. The first studies on this are promising, but since rapamycin has very strong side effects and requires a prescription, you should definitely not experiment with it.
Another method of keeping mTOR levels low is e.g.b the 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. This includes, among other things, Berberine.
Of nutrient abundance and nutrient scarcity
mTOR, like IGF-1, must be downregulated in order to produce corresponding positive effects on aging. While IGF-1 (presence of glucose) and mTOR (presence of Amino acids) signal nutrient abundance, AMPK and sirtuins signal nutrient shortage (absence of energy). As a result, 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 most well-researched diabetes medications. In worms and mice without previous diabetic disease, administration of metformin extended lifespan.
Did you know? Green Tea has been considered healthy for centuries and scientists have now been able to identify the active ingredients behind it. The theanine contained in green tea has a calming effect and can act in the same way as EGCG have a positive effect on blood sugar metabolism.
Gandhi, fasting and the future
Overall, the currently available scientific information supports the idea that the regulation of nutrient intake contributes to a longer, healthy life. In addition, the research results based on the active ingredients rapamycin and metformin are as impressive as they are promising.
Although a lot of detailed research is still missing, from the current perspective it can be said that our fifth hallmark of aging is also a promising starting point for influencing aging – right now. After all, the positive effects of fasting are already evident and understandable at this point in time.
Mahatma Gandhi once said:
“Lent is part of my being. I can't do without them any more than I can do without my eyes. What eyes are to the external world, fasting is to the internal world.”
What was spiritual then is now biochemical reality… at least the second part.
The next article in this series will focus on the sixth hallmark of aging: Mitochondrial dysfunction.
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