In this text about the regulated measurement of nutrients as the fifth hallmark of ageing, we need to delve a little deeper into the biochemistry of the cell. Don't worry, it sounds worse than expected, 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 about this in our article on the four longevity pathways.
But even without this article, by the end of this article you will know why calorie restriction has led to longer lives in so many animals. The Nobel Prize in Physiology and Medicine awarded in 2016 proves 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 advancing the understanding of autophagy.
This is a process, in which damaged cell components are broken down when cells are "starved"for a certain period of time. This allows aged cells to regain their functionality - a kind of recycling program.
Fasting means more than autophagy. There is a lot hidden in the shallows of molecularity when it comes to the connection between fasting and longevity. 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 ageing.
Hormones and their axes
There are countless hormones in the body that control processes such as muscle growth, menstruation or digestion. In most cases, however, hormones do not have a direct effect. They are very often organized along so-called axes or pathways, which means that one hormone stimulates another hormone and so on up to the end organ where a hormone then exerts its effect.
So that you don't have to study a whole lecture on the subject, let's focus on a hormone axis related to longevity research.
Did you know If our body produces too much of the growth hormone GH in adulthood, this can lead to the clinical picture of acromegaly . The hands and face are usually affected first and become abnormally large. The cause is usually an autonomous overproduction of GH in the pituitary gland.
The somatotropic axis: GH and IGF-1
The somatotropic axis comprises the growth hormone (GH), 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 now released by the pituitary gland and this in turn stimulates cells (primarily 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 the characteristic name. So when we eat something, our blood sugar and therefore also IGF-1 and insulin.
The two main effects of IGF-1 that are of interest to us are shown in the diagram. On the one hand, the FOXO family of transcription factors is inhibited and on the other, mTOR is activated.
Before we confuse you with more complicated names, let's start with a brief explanation. FOXO stands for Forkhead box Class O and in the form for a series of transcription factors. These molecules can switch certain sites on 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 conferred a survival advantage.
Excursus: Evolutionary conservation
Evolutionary preservation has nothing to do with the preservation of food, but is similar in meaning to the term we know. 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 gains a selection advantage and the others die out. Nowadays, this selection pressure is somewhat overriddenby the highly developed medical possibilities. Anyone who had a heart attack in the Stone Age was almost certain to die - today there is intensive care medicine and a range of drugs to prevent this.
Studies have now made some interesting findings in this context. Small genetic mutations that reduce the function of IGF-1 have been linked to longevity in both humans and model organisms. This is remarkable and also highlights the importance of such pathways for a long and healthy life.
IGF-1 Signalweg
The following result has been repeatedly replicated in numerous studies: A weakening of the IGF-1 signaling pathway consistently extends the lifespan of flies, worms and also mice, for example. Among other things, 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 are therefore unable to 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 easy if that were all there was to it. As we get older, we would expect to find high IGF-1 levels based on the above findings as this signaling pathway is one of the causes of aging. This is precisely the crux of the matter
Some other studies have described that during the normal ageing process GH and IGF-1 levels fall. The concentration also decreased in mice with accelerated ageing. So do we have to discard our theory about ageing and higher IGF-1 levels?
Not according to proponents of the following theory. According to this theory, organisms with lower IGF-1 functionality can survive longer in old age because this results in slower cell growth and a slower metabolism. This ultimately means less cell damage, which in turn is good for us.
The body therefore 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 required, 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 therefore no longer mutually exclusive, but complement each other.
Did you know A varied and plant-rich diet contributes significantly to healthy ageing. The signaling pathways that can be activated by food are diverse. One of them is the IGF-1 pathway. The sulforaphane contained in broccoli was able to prolong the life of C.elegansin 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, the focus is on three other related and interconnected nutrient sensing systems:
- mTOR is used to detect high amino acid concentrations - thus rises after a high-protein meal.
- AMPK recognizes low energy states through high AMP levels. AMP is produced during the consumption of the body's most important energy source, ATP.
- Sirtuins , also known as longevity genes, recognize low energy states by sensing high NADlevels.
When mTOR is downregulated, yeasts, worms and flies live longer. MTOR can be specifically inhibited by the drug 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 treatmentare worrying. Poorer wound healing, insulin resistance and cataracts send their regards.
Despite this, rapamycin is the most robust chemical intervention ever discovered to extend lifespan in mammals. This makes it all the more important to understand the mechanisms involved to determine the extent to which deleterious and beneficial effects of mTOR inhibition can be separated
Did you know The American physician and longevity expert Peter Attia dedicates an entire chapter to rapamycin in his successful book "Outlive". The initial studies are promising, but as rapamycin has very strong side effects and is available on prescription, it should not be experimented with under any circumstances.
Another method of keeping mTOR levels low is z.Bfasting. However, 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 the berberine.
Of nutrient abundance and nutrient scarcity
mTOR, like IGF-1, must therefore be downregulated in order to have positive effects on ageing. While IGF-1 (presence of glucose) and mTOR (presence of amino acids) signal nutrient abundance , AMPK and sirtuins signal nutrient scarcity (absence of energy). Consequently, a stronger effect of AMPK and sirtuins favors 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 prolonged life span.
Did you know Green tea has been considered healthy for centuries and scientists have now been able to identify the active ingredients behind it. For example, theanine contained in green tea has a calming effect and, like EGCG , can have a positive effect on blood sugar metabolism.
Gandhi, fasting and the future
All in all, the scientific information currently available 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 some detailed research is still outstanding, it can be said from the current perspective that our fifth hallmark of ageing is also a promising starting point for influencing ageing -right now. After all, the positive effects of fasting are already evident and comprehensible at the present time.
Mahatma Gandhi once said:
"The fasts are part of my being. I can no more do without them than I can do without my eyes. What eyes are to the outer world, fasting is to the inner world."
What was spiritual back then is now a biochemical reality... at least the second part.
The next article in this series is about the sixth hallmark of aging: Mitochondrial dysfunction.
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