In this text about the deregulated nutrient measurement as the fifth hallmark of aging, we need to dive a little deeper into the biochemistry of the cell. Don't worry, it sounds worse than it is, but to better understand the Hallmarks of Aging, we need a few technical terms, such as mTOR, Sirtuins, IGF-1, or AMPK. You can learn 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 a longer life in so many animals. That certain forms of fasting and caloric restriction have far-reaching significance for the general public is evidenced by the Nobel Prize in Physiology and Medicine awarded in 2016. Yoshinori Ohsumi, a Japanese cell biologist, received the prestigious award for his achievements in the expanded understanding of autophagy.
This is a process, in which damaged cell components are broken down when cells "starve" for a certain period of time. This allows aged cells to regain their functionality – a kind of recycling program.
Fasting means more than just autophagy. In the question of the connection between fasting and longevity, a lot is hidden in the depths of molecularity. We will dive 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 thus combats aging.
Hormones and their axes
In the body, there are countless hormones that regulate processes such as muscle growth, menstruation, or digestion. However, hormones usually do not exert their effects directly. They are often organized along so-called axes or pathways, which means that one hormone stimulates another hormone, and so on, until the target 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 is related to longevity research.
Did you know? If our body produces too much growth hormone GH in adulthood, it can lead to the condition of acromegaly . The hands and face are usually the first to be affected 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 English insulin-like growth factor). In the context of this axis, GH is released by the pituitary gland, which in turn stimulates cells (especially liver cells) to produce IGF-1.
The signal transduction 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, blood sugar levels inevitably rise and thus also IGF-1 and insulin ..
The two main effects of IGF-1 that are interesting to us are shown in the diagram. On 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, a brief explanation first. FOXO stands for Forkhead box Class O and refers to a series of transcription factors. Such molecules can turn certain sites on or off on our DNA. You can learn more about this in the article on epigenetic changes.
The name mTOR stands for mammalian Target of Rapamycin. It is named after the discovery that the drug Rapamycin binds to this receptor. More on that later. Both signaling pathways are involved in aging and have been conserved through evolution, as they have provided a survival advantage.
Excursus: Evolutionary Conservation
Evolutionary conservation has nothing to do with food preservation, but it is similar in meaning to the term we know. More specifically: In evolution, there is constant selective pressure, and only the most functional organisms survive.
If certain genetic sequences or signaling pathways occur over millions of years, it means that an organism gains a selective advantage and the others become extinct. Nowadays, this selective pressure is somewhat mitigated by highly developed medical possibilities.Whoever had a heart attack in the Stone Age almost certainly died – today there is intensive care medicine and a range of medications that can 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 highlights the importance of such pathways for a long and healthy life.
IGF-1 signaling pathway
In numerous studies, the following result has been repeatedly replicated: A weakening of the IGF-1 signaling pathway consistently extends the lifespan of, for example, flies, worms, and also mice.This has to do, among other things, with the transcription factor FOXO , which has also been widely studied. Under normal circumstances, IGF-1 inhibits the FOXO family, and therefore the transcription factors cannot exert their effects. If the IGF-1 signaling pathway is inhibited, then FOXO can work and ensure that proteins are produced from DNA that counteract the aging process .
The Paradox
However, it would be too simple if that were all there was to it. As we age, based on the above findings, we would expect to find a high IGF-1 level, as this signaling pathway is causally related to aging . This is exactly where the catch lies.
Some other studies have described that during the normal aging process, GH and IGF-1 levels decrease. Even in mice with accelerated aging, the concentration decreased. So do we have to discard our theory about aging and higher IGF-1 levels?
Not if it depends on representatives of the following theory. According to this, 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 is good for us.
The body helps itself once again by simply downregulating the signaling pathway with age to keep damage low. As so often, the balancing abilities of our body are called into question, as extremely low IGF-1 levels are not compatible with life.This is quite logical when one recalls the influence of IGF-1 on metabolism and cell growth. The different study results no longer contradict each other but complement one another. Did you know? A varied and plant-rich diet significantly contributes to our healthy aging. 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 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 measurement, three other related and interconnected nutrient sensing systems are at the forefront:
- mTOR is responsible for sensing high amino acid concentrations – therefore increases after a protein-rich meal.
- AMPK detects low energy states through high AMP levels. AMP is produced during the consumption of the body's most important energy carrier, ATP.
- Sirtuins, also known as longevity genes, detect low energy states by sensing high NAD levels.
If mTOR is downregulated, then longer lifespans are observed in yeast, worms, and flies. mTOR can be specifically inhibited pharmacologically by the active ingredient Rapamycin . This mechanism of action is utilized in transplant surgery. After kidney transplants, Rapamycin is an important immunosuppressant to prevent the foreign kidney from being 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 concerning.Poor wound healing, insulin resistance and cataracts are a concern here.
Nevertheless, rapamycin is the most robust chemical intervention ever discovered for extending lifespan in mammals. It is 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 from each other
Did you know? The American physician and longevity expert Peter Attia devotes an entire chapter to rapamycin in his successful book "Outlive." The initial studies are promising, but since rapamycin has very strong side effects and is prescription-only, one should definitely not experiment with it.
Another method to keep mTOR levels low is z.B. fasting. But also so-called fasting mimetics (molecules that trick the body into thinking it is in a fasting state) can keep mTOR levels low. This includes, among other things, berberine.
Of nutrient abundance and nutrient scarcity
mTOR must therefore be downregulated just like IGF-1 to induce correspondingly positive effects on aging. While IGF-1 (Presence of glucose) and mTOR (Presence of amino acids) signal nutrient abundance, AMPK and sirtuins report nutrient scarcity (Absence of energy). Consequently, a stronger effect of AMPK and sirtuins promotes healthy aging.
The AMPK level is increased, for example, by metformin. The medication is one of the oldest and most well-researched diabetes medications. In worms and mice without pre-existing diabetes, the 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 positively influence blood sugar metabolism just like EGCG . Pure Theanine from green tea is also included in our L-Theanine capsules.
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.Furthermore, the research results based on the active ingredients Rapamycin and Metformin are as impressive as they are promising.
Although there is still a lot of detailed research to be done, it can be said from the current perspective, that our fifth hallmark of aging is also a promising starting point for influencing aging – and that is already the case now. After all, the positive effects of fasting are already evident and understandable at this point.
Mahatma Gandhi once said:
“The times of fasting are part of my being. I cannot do without them any more than I can do without my eyes. What the eyes are for the outer world, fasting is for the inner.”
What was spiritual back then is biochemical reality today… at least the second part.
The next article in this series is about the sixth hallmark of aging: Mitochondrial Dysfunction.
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