Dietary restriction --- counter-intuitive way to longevity and promoting health

Ageing is an inevitable aspect of life. Everyone must go through it. But some surprisingly age longer than the rest of us. For example, Jeanne Calment from France lived up to 122 years old and was crowned the oldest people on earth. But often long lifespan inevitably associated with disabilities and disease. Is it possible to have the bests of both worlds? Both lifespan and "health" span?

Scientists might have some answers. In this paper published by Luigi Fontana, Division of Geriatrics and Nutritional Science, Washington University School of Medicine, the researchers showed that dietary restriction/DR, meal timing is able to promote health and increase lifespan. Actually, this research is not the first in existence to prove such theory, this concept was actually proven 80 years ago by extending the lifespan of rats. Approximately 30% of DR animals dying at old age shows no pathological lesion compared to 6% of those who fed ad libitum(with desires). The same result can be seen with yeast and monkeys too! Is dietary restriction the key to longevity?

Nutrient-sensing pathways

This table illustrates the results of successful intervention method used to achieve longevity and the affected mechanism of action. And this is all tested on animal models as it is difficult to experiment in live humans. If you pay particular attention to the mechanism of action. You will see the most recurring mechanism of action is decreasing nutrient-sensing pathway. This proves to us that this is a key element to achieve longevity with promoted health. So what is nutrient-sensing pathway?

Nutrient-sensing is the cell ability to recognize and respond to food/nutrients consumed by the organisms. What are their functions? These pathways exist so that the cells will know when to process the available food and signal the cells to use them to grow. When the nutrient availability is low, it will start breaking down its own cells to keep the organisms alive. This is an evolutionary conserved metabolic pathway that enabled our ancestors to survive through scarcity of foods. So there is 2 main nutrient-sensing pathway :

mTOR(Mammalian Target of Rapamycin)

mTOR pathway is responsible for sensing the availability of amino acids, glucose and protein synthesis. In an ageing person, some studies suggested that mTOR activity increases and maintain at a high level of protein synthesis. It is hypothesized that mTOR is an example of antagonistic pleiotrophy.

Pleiotrophy refers to one gene which controls a lot of traits. These traits can either be helpful to the organisms or detrimental to the organisms(human). Therefore, translation of one gene will produce a balance between two traits. It will act as a constraint on a "nature-selected" perfect organisms. In case of mTOR, high level of activity in this pathway is meant to produce a balance between health and gradual loss of function.

Yes without antagonistic pleiotrophy, natural selection can produce HULK!

Scientist found that by blocking this pathway, mTOR will actually promote autophagy instead of producing more proteins, and also upregulates glycolysis! This meant that our body will have more time to remove its dysfunctional cellular components. Moreover, high activity of protein synthesis is also related to higher tumorigenesis.

And the best way to block mTOR pathway? Yes it's dietary restriction! Humans have been using fasting as a method to cleanse their body since antiquity.

AMPK pathway (The energy sensing pathway)

AMPK is a high energy conserve maniac that regulates the energy homeostasis in the cells. When it senses low energy available in the cells (energy in cells are in the form of ATP), AMPK will go up. AMPK will start to find ways for more ATP to be produced and coordinates decrease in ATP usage. This is realized by inducing mitochondrial biogenesis or formation of new mitochondria. Mitochondria is a powerhouse in cells to produce ATP.

Simultaneously, old mitochondria will also be broken down through mitophagy(selective autophagy of dysfunctional mitochondria). So as the new mitochondria are there to replace the old one, the old one will be eliminated. This will produce a complete renovation of mitochondrial pool.

This is essential because: Aging is associated with a loss of mitochondrial network homeostasis. Mitochondria are able to fuse together or break apart from each other (fission) in healthy living organisms. We can see a lot of abnormally shaped or even swollen present mitochondria present in old person. This disruption to mitochondrial dynamics are often associated to neurodegenerative disease such as Alzheimer's or Parkinson.

Therefore, inducing mitochondrial biogenesis by activating AMPK pathway is beneficial to aging person. Clunky dysfunctional mitochondria will be eliminated together with the disease while stimulating the growth of new functional mitochondria. It's like having a new car engine all over again. Revived from the dead.

In this diagram, you just have to focus on the AMPK activating more than one gene responsible for longevity

Fasting as a better way to inhibit nutrient-sensing pathway

By now, you should understand by inhibiting or decreasing nutrient sensing pathway intermittently will have positive effect on longevity. Therefore, dietary intervention in its more natural way, INTERMITTENT FASTING is a more effective way to achieve longevity. This is because all nutrient-sensing pathway can be inhibited all at once. Theoretically eating less frequently will improve your health!

Ancestral humans are designed to eat intermittently depending on food availability. Ancient humans are hunter-gatherer, sometimes worsening of climate doesn't allow them to hunt. They need to starve for days in order to survive. That explains our well-developed food storage system in our body. Just look at glycogen in the liver and body fat. They are all storage of energy utilized in time of starvation.

However, things get a little bit better with the emergence of agriculture approximately 10,000 years ago. Agriculture allows people to have a more stable food availability. However, there will still be seasonal availability of food which may result sometimes weeks or months of inadequate food. This proves throughout history our body is trained to starve.

Nowadays, we are bombarded with all kinds of food we see from ads. We are oversupplying ourselves with foods. No wonder all type of cancer is more evident in our era. Not back in ancient times.

Return of ancient diet? Possible?

CONCLUSION

Ageing with disease and disabilities might seem like a far-fetched idea. But at least for now, we understand that diet plays a major role in ensuring longevity in humans. Excessive eating will only bring us more diseases. While intermittent fasting might be the key to a longer lifespan while maintaining good health! Thanks to our latest understanding on nutrient-sensing pathways. We can begin to regain some of the lost wisdom by following the ancient way of diet that is taking a break from eating too frequently!

REFERENCES :
Promoting Health and Longevity through Diet: from Model Organisms to Humans
Luigi Fontana

Mitochondrial stress signaling in longevity: A new role for mitochondrial function in aging

The general amino acid control pathway regulates mTOR and autophagy during serum/glutamine starvation
Rui Chen

Nutrient Sensing Mechanisms and Pathways
Alejo Efeyan

IMG SRC : 1, 2, 3, 4, 5, 6, 7