"Nature" sub-issue: the scientific idea of "opening the valley" to extend life! Xiada Lin Shengcai's team has developed the "Grain Extract", which can simulate the effect of calorie restriction, which can reduce sugar and weight, and make mice live a long and healthy life

*For medical professionals only

Speaking of calorie restriction, whether you are a dieter or a health expert, you must raise your little hand to prepare to answer the question
.
Fasting and other ways to "keep the body hungry" and restrict calorie intake have been shown to have the effects
of weight loss, blood sugar control, anti-aging, and life extension in a variety of model organisms.

However, the difficulty of "keeping your mouth shut" must be known
to everyone.
In the face of the temptation of roasted wings, potato chips, and milk tea, it is "beckoning and stopping
.
" Every time I go to the dim sum area, deli area, and snack area of the supermarket after work, I feel dizzy, as if this is a red light district
.

Do we still have medicine?

Yes, this can be
.
Academician Lin Shengcai's team of Xiamen University and Deng Xianming's team joined hands to develop Aldometanib, a drug that simulates fasting, which Chinese translated as "Peeling the Valley Essence"
.

Aldometanib is a novel AMPK activator that specifically activates protein kinase AMPK
in lysosomes by inhibiting the binding of aldolase to fructose 1,6-bisphosphate (FBP), producing false signals similar to starvation or caloric restriction.
Aldometanib not only has the effect of lowering blood sugar and losing weight, but also can effectively relieve fatty liver and non-alcoholic steatohepatitis in mice, and long-term use can significantly extend the healthy life span of mice [1].

The article was published yesterday in the journal Nature Metabolism
.

Screenshot of the front page of the paper

AMPK is a highly conserved and important energy receptor in eukaryotic cells, sensing changes
in glucose levels and energy status within the cell.
AMPK is activated
when glucose is depleted and the AMP/ATP, ADP/ATP ratios increase.

After AMPK is activated, it can regulate multiple downstream pathways to maintain homeostasis, can inhibit fat synthesis, promote lipolysis, etc.
, and is also related
to anti-aging mechanisms such as promoting autophagy and inhibiting inflammatory response.
These make AMPK a potential therapeutic target for metabolic disorders such as diabetes, fatty liver, and obesity, and the power of calorie restriction is also achieved by activating AMPK [1].

However, in 2017, Academician Lin Shengcai's team found a unique way to activate AMPK, the lysosomal pathway (named "Lin Pathway").

They found that aldolase is an important sensor for
cells to feel glucose starvation.
Regardless of energy scarcity (i.
e.
, independent of the AMP/ADP ratio), when glucose levels decrease, aldolase no longer binds to fructose 1,6-bisphosphate (FBP), but specifically activates AMPK in lysosomes [2].

Aldolase senses glucose levels, thereby specifically regulating AMPK in lysosomes[2]

Follow-up studies have shown that calorie-restricted diets and the glucose-lowering drug metformin use this unique pathway to activate AMPK
.
The former causes glucose starvation, while the latter activates AMPK in lysosomes by binding to the protein PEN2 [3].

In this case, the adverse effects of widespread activation of AMPK or excessive suppression of mitochondria (in order to increase AMP levels) can be avoided, and multiple health benefits
can be obtained.

This time, Lin Shengcai, Deng Xianming and others tried to find a breakthrough in the lysosomal pathway, by inhibiting the binding of aldolase and FBP, creating the illusion of caloric restriction for cells and activating AMPK
.

They screened and optimized more than 5,000 compounds to obtain the compound Aldometanib, which has the best aldolase inhibition
.

In vitro experimental results showed that aldometanib was enriched in lysosomes in human embryonic kidney cells (HEK293T), mouse embryonic fibroblasts (MEF), mouse primary hepatocytes and mouse primary skeletal muscle cells, which may be related to
the pH environment.
When the concentration of aldometanib in cells ≥5 nM, it can pass through the lysosomal pathway, inhibit only aldolases in lysosomes, and specifically activate lysosomal AMPK
.

The essence of the valley

At the same time, no increase in the AMP/ATP, ADP/ATP ratio was observed in these cells, unless the concentration of aldometanib reached 200 nM and above
.

In this way, Aldometanib can indeed imitate the "face" of calorie restriction, but can it imitate the "taste" of calorie restriction?

Subsequently, the researchers conducted a series of tests
on the efficacy of Aldometanib in mouse experiments.

The results showed that short-term administration of Aldometanib had a hypoglycemic effect, which could directly promote glucose absorption and significantly reduce fasting blood sugar, improve insulin and improve glucose tolerance without stimulating insulin secretion
.

There is a hand in reducing sugar by grain refinement

For obese mice, Aldometanib was able to reduce food intake, promote white fat browning in the groin, increase average daily energy expenditure, and reduce intestinal fat absorption
.
If the drug is continued for 1 month, it can significantly reduce the weight, fat mass and body fat rate
of obese mice.

Pi Gu Jing has a hand in weight loss

Not only that, Aldometanib was also able to reduce fatty liver and nonalcoholic steatohepatitis symptoms
in mice.
Once AMPK is knocked out of the liver, aldometanib cannot use its fists
there.

Of course, there are also the things
that everyone is most concerned about about life.

The researchers added 100 μg/ml of aldometanib to the drinking water of aged mice (1 year old) for long-term treatment
.
The results showed a significant increase in lifespan of these older mice, with male mice 7.
4% longer and female mice 7.
7%
longer.
In addition, after taking the drug, the aging-related mitochondrial dysfunction was improved, and the running distance, running duration and grip strength were also significantly increased, which verified the anti-aging effect
of aldometanib.

There is a hand in the fight against aging

Notably, aldometanib did not cause myocardial hypertrophy in mice compared to other drugs that did not specifically activate AMPK [4], and no ECG abnormalities or cardiac insufficiency
were observed in treatment.
Compared to metformin, which also takes the lysosomal pathway to activate AMPK, aldometanib has a
wider range of effects.
The effect of metformin is limited to the liver, kidneys, and intestines, while aldometanib can be found in
multiple tissues and organs.

In general, Lin Shengcai, Deng Xianming and others have developed a new AMPK activator based on the lysosomal pathway, a unique pathway for calorie restriction to activate AMPK, to transmit false signals of hunger to cells, so as to obtain the multifaceted and safe health benefits of calorie-restricted diets.

In mice, aldometanib has the effects of lowering glucose, losing weight, and prolonging life without obvious side effects
.

Researchers have expectations for Aldometanib, believing that these properties make it promising to be developed as a new drug
for the treatment of metabolic diseases in humans.
Singularity cake is also full of expectations, eat and drink without delay, taking medicine can deceive AMPK, make the body think that we are fasting, can steal the fun
.

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References:

[1] #MOESM1

[2] Zhang, CS.
, Hawley, S.
, Zong, Y.
et al.
Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK.
Nature 548, 112–116 (2017).

[3] Ma, T.
, Tian, X.
, Zhang, B.
et al.
Low-dose metformin targets the lysosomal AMPK pathway through PEN2.
Nature 603, 159–165 (2022).

[4] Myers, R.
W.
et al.
Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy.
Science 357, 507–511 (2017).

The author of this articleZhang Eddy