"Healthy and longevity!" Lin Shengcai's team and Deng Xianming's team developed a new AMPK activator that mimics the effect of Pinggu

As the old saying goes, "The period of profit and contraction is not only in the sky, but also in the blessing of nourishment, but also in eternal years" (Cao Cao, "Turtle Although Life").

Healthy and longevity have been the pursuit
of small human beings to fight and integrate with the mysterious and magnificent nature since ancient times.
In history, Qin Shi Huang was famous for his persistent pursuit of immortality, and also left behind the story
of refining elixirs and sending Xu Fu to cross the ocean to seek the elixir of life.

Academician Lin Shengcai of our institute cooperated with Professor Deng Xianming, after six years of hard work, combined with physiological conditions such as valley opening and calorie restriction, based on the new pathway of AMPK activation in the body opened up by Lin Shengcai's research group in recent years, developed an AMPK activator - "Aldometanib", which Chinese translates as "valley extracting essence" (Figure 1), and is very likely to realize the dream
of human health and longevity 。 This article was published online in Nature Metabolism on October 10, 2022 under the title The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK
.

Why is it called "Peeling the Valley"?

Figure 1.
The chemical structure of "Grain Cracker"

This is precisely because the AMPK it activates is a key protein
in the body that maintains metabolic homeostasis.
AMPK in cells or bodies is activated in a state of starvation and calorie restriction, commonly known as valley opening
.
In cells, AMPK is much like a switch, turned on
once the cell encounters a nutrient and energy deficiency.
When it is turned on, the energy-producing catabolism in the cell is promoted, while the energy-consuming anabolism is inhibited, which allows the energy level of the cell to be maintained, that is, to reach "metabolic homeostasis"
.
We experience a nutritional "deficiency" every day, and this usually refers to a decrease in glucose intake levels – for example, between meals, after exercise, etc.
, and this is when AMPK is activated and comes into play: AMPK breaks down fat and protein for energy while inhibiting their synthesis
。 More importantly, with the great abundance of modern living materials, metabolic diseases caused by hyperglycemia, hyperlipidemia, fatty liver and other metabolic diseases caused by excess nutrition have become important factors affecting people's quality of life, and recent studies have shown that many types of tumors, and even aging, can also be attributed to metabolic disorders
.
The functions of AMPK in inhibiting fat synthesis and promoting lipolysis can restore the metabolism in these diseases from a disordered state to normal homeostasis, especially by inhibiting the activity of mTOR, another protein that promotes anabolism and cell proliferation, which can alleviate the above symptoms and even prolong life
.
It is by simulating calorie restriction that it creates a "fake hunger" similar to when glucose levels drop—even when you're fed and drunk—that activates AMPK
.
Just as the sage of Kong left thousands of years ago, "Food can nourish people, but it can also hurt people; The way to adopt is more important than moderation
.
Like the proverb, the aptly named "Breaking the Grain" is taken from this
.

So, how does "Peeling Valley" achieve health and longevity?

This can be traced back to the research
on the activation mechanism of AMPK in cells and in the body that began more than ten years ago by Academician Lin Shengcai's team.
Through these years of research, they gradually discovered the mechanism of how AMPK senses glucose levels and is activated
.
Recently, this mechanism has been named "Forest Pathway"
.
The discovery of the forest pathway has changed people's understanding of
AMPK activation.
The classical view is that the opening of AMPK is only related to the intracellular energy level, that is, when the energy level decreases, the level of ATP, the energy supply substance in the body decreases, and the level of ADP and AMP, the hydrolysate products after ATP energy supply, rises
.
According to biochemical principles, the rise in ADP levels further causes a sharp rise in AMP levels, which binds to AMPK and causes the activation of AMPK, which is where the name AMPK comes from
.
For this reason, AMPK has always been mistaken for activating AMPK
only when energy levels drop.
Lin Shengcai's team found that when glucose levels dropped, AMPK could be activated before ATP levels dropped, replenishing the deficiency of potential ATP in
time.
Correspondingly, the decrease in glucose levels at this time is due to the decline in the level of fructose 1,6-bisphosphate through its metabolites, glycolytic pathways, which further leads to more and more aldolases that catalyze fructose 1,6-bisphosphate becoming unbound by fructose 1,6-bisphosphate, transmitting this signal through a series of molecular mechanisms to activate the AMPK protein complex and activating AMPK (Figure 2).

It can be seen that the forest pathway is a precise and sensitive way to regulate AMPK, which helps our body to respond quickly to the lack of nutrients, initiates the role of AMPK and the related process
of maintaining metabolic homeostasis.
In addition, compared with the classical pathway, the Linting pathway also has the property of activating AMPK in a specific region, that is, it activates not all AMPK in the whole cell, but only a small part of the AMPK localized on the organelle of lysosomes (Figure 2).

As mentioned later, it is this unique property of the forest pathway that provides the principles and ideas for the development of clinically significant AMPK activators, otherwise the cells will activate all AMPK "libraries" at every turn, which will cause side effects
such as myocardial hypertrophy.

Figure 2.
AMP is activated when the air conditioning is controlled
.
The valley removal process only activates AMPK on lysosomes through the Lintanway and does not affect AMPK activation
in other parts.

In fact, before the discovery of the forest pathway, people had been working
on the classical activation pathway for nearly three decades.
Countless drug development companies have a romantic belief that AMPK activators can treat a variety of diseases and have longevity effects - and have invested a lot of manpower and material resources to obtain AMPK activators
.
Among them are many drug giants
such as Merck and Pfizer.
However, it was previously understood that activating AMPK by reducing ATP levels in cells requires inhibition of important metabolic sites and pathways such as mitochondria, which inevitably leads to serious toxicity (many mitochondrial inhibitors are highly toxic, such as paraquat).

Second, directly targeting AMPK and indiscriminately activating all AMPK in cells often causes unexpected side effects - such as MK-8722, which is currently closest to clinical application, causes adverse reactions
such as myocardial hypertrophy.
Lin Shengcai's team believes that this is likely to be due to the indiscriminate activation of AMPK caused by too strong reaction, which is counterproductive: just like the current connected to the switch, it cannot float up and down too much, if the current is too large, it will burn out the switch, too small to work
.
This view can also be seen
from the fact that only part of AMPK is activated through the forest pathway to exercise beneficial effects during hunger and valley opening.
As another evidence, metformin itself is not an activator designed for AMPK, nor does it directly bind to AMPK, but it exercises multifaceted metabolic benefits through AMPK and is known
for its safety.
The recent research results of Lin Shengcai's team also found that metformin does not actually increase AMP, but by targeting the forest pathway, triggering the activation
of AMPK.
The above studies show that designing the activator of AMPK through the activation mode of AMPK, which commonly occurs under the condition of glucose decline, will make it possible to imitate the scene where AMPK activates and exercises many beneficial effects under physiological conditions, and solve the problem
that the classical approach cannot solve.

On this basis, Lin Shengcai's team screened the aldolase inhibitor of aldolase in a large drug library for the aldolase receptor in the Lin pathway, together with the Deng Xianming team, who is good at drug development, and verified that the inhibitor can inhibit fructose 1,6-bisphosphate binding aldolase in a number of mammalian cells through molecular biology, thereby simulating the activation scene
of AMPK when glucose levels decrease 。 In addition, it also has the characteristic of being able to specifically inhibit aldolases on lysosomes without affecting other aldolases involved in normal glucose metabolism, thus avoiding the disorder of cell metabolism caused by comprehensive inhibition of glycolysis
.
Team members are often amazed by such a miraculous place of action and call it a
godsend.
Compared with metformin, "Pingolin" is not limited to the liver and intestines, but can enter multiple tissues and organs, including muscles, fat, and even immune cells, so that it can exercise a wider range of effects
than metformin.

What are the effects of "Extracting Grain Essence"?

The team of Lin Shengcai and Deng Xianming not only verified the activation effect of "Peeling Grain Essence" on AMPK at the cellular level, but also tested the physiological functions
of "Pilling Grain Essence" through AMPK on mice, rats and C.
elegans model animals.
They found that in obese mice and rats induced by a high-fat diet induced by overnutrition, "Pingel" was able to significantly lose weight, lower blood sugar, relieve fatty liver and insulin resistance, the latter being one of the important phenotypes of
diabetes.
However, when the AMPK gene is removed in the liver or muscle, "Peeling Grain Essence" is ineffective, indicating that "Peeling Grain Essence" exercises its function
through AMPK.
More importantly, by activating AMPK, the lifespan of nematodes is significantly extended, and the level of NAD⁺ and the number and function of mitochondria of longevity-related metabolites in the body are also significantly improved, which fully reflects the effect
of "Grain Extract" in promoting health and longevity.
In order to finally determine the possible safety of activating AMPK through the forest pathway, they spent nearly five years alone feeding mice long-term and tracking the physiological characteristics
of these mice for a long time.
They found that feeding one-year "Grain Extract" (equivalent to half the life span of normal mice) significantly increased the life span of mice without observing any side effects such as myocardial hypertrophy (Figure 3), thus laying a foundation
for the further development and clinical application of "Grain Essence".
They also observed a significant improvement in muscle strength and exercise capacity in the administered mice (Figure 4).

As one of the important indicators of aging, the results show that "Peeling Grain Essence" not only prolongs the life of mice, but also delays the aging
of mice.
Finally, the team cautions that mice may live more drastically
if they invest more money and time to conduct more detailed research, such as adjusting the starting time and dose of the drug.

Figure 3.
"Grain Extract" can effectively prolong the life of mice

Figure 4.
"Grain Cracking" improves the exercise ability of elderly mice (such as running distance; left) and muscle strength (such as grip; Right)

In short, by threading needles and threads, targeting aldolase, an indirect means of glucose receptors, in the forest pathway, the "Peeling Grain Essence" avoids the side effects of the classical pathway activation of AMPK, and activates AMPK in a "natural way" way, thereby maintaining the health and longevity of the organism (Figure 5).

Figure 5.
"Valley" activates the pattern diagram
of AMPK through the "Forest Pathway".
The figure shows that "Aldometanib", or "Extract", by inhibiting aldolase (ALDO) binding to the glucose metabolite FBP (fructose-1,6-bisphosphate), thereby believing that the cells are starving, initiating the AMPK activation program, thereby reducing glucose, relieving fatty liver, prolonging life and other benefits
.

At present, Lin Shengcai's team is intensively carrying out preclinical research on "Peeling Grain Essence", and has observed that "Peeling Valley" has significant weight loss, improvement of fatty liver, and anti-tumor (liver cancer) effects
.
We look forward to "Peeling Valley" to enter clinical trials as soon as possible to benefit the majority of patients with
metabolic diseases.
"

Links to papers: https://doi.
org/10.
1038/s42255-022-00640-7

BioArt link: https://mp.
weixin.
qq.
com/s/EcUnPeayzgwpFmoIQ6n6zg

(Photo/Text BioArt public number/Lin Shengcai Research Group edited by School of Life Sciences, Xiamen University)