This article is from WeChat official account:Geekheal (ID: geekheal_com) , author: Tan Master, the original title: “ heavy: adjust the immune cell metabolism, or can reverse brain aging! Stanford scientists have discovered that restoring the abnormal metabolic state of myeloid cells such as macrophages can reverse aging-related cognitive decline. The first picture is from: “Super Body” stills

No one wants to grow old, whether it’s body or mind, it’s okay to age slowly. Therefore, the four words “reverse aging” have attracted countless people. Of course, for the singularity cakes, only methods with scientific evidence count.

So seeing a new study published by Nature today, Singularity Cake must be introduced. This study from the Stanford University team shows that “returning the metabolic state of myeloid immune cells such as macrophages to a young state” may be able to reverse brain aging and combat Alzheimer’s disease.(AD).

This study found that immune cells such as macrophages and microglia in the brain and other parts of the body will undergo changes in their metabolic state with aging, converting more glucose into glycogen storage, resulting in themselves There is a problem with the energy supply.

The normal work of immune cells requires a lot of energy, and the state of immune cells with insufficient energy is of course not good. For example, the phagocytosis of macrophages will decrease, and they will also transform into a pro-inflammatory phenotype, thereby promoting aging Related chronic inflammation.

In the change of the energy status of immune cells, the inflammatory mediator prostaglandin E2(PGE2) played a key role, so inhibiting PGE2 or its corresponding receptor EP2 not only significantly improved the chronic inflammation state of aging mice, It also reversed the decline in cognitive function[1]. If the immune cells are young, the brain will be young.

The breakthrough point of the Stanford team’s research is actually PGE2. Previous studies have shown that patients with neurodegenerative diseases such as AD have higher expression levels of PGE2[2]. This may also explain that in some studies, long-term use of aspirin is associated with a decreased risk of AD [3] because aspirin inhibits The COX-2 is the upstream signal of PGE2.

Aspirin, COX-2, PGE2 and EP2 Relationship

The research team believes that the effect of PGE2 on brain aging is carried out by changing the metabolic state of immune cells. Therefore, it first compared the monocyte-derived cells in people over 65 and under 35. Macrophages (MDMs) found that the synthesis of PGE2 by MDMs in people over 65 years old increased significantly.

Use PGE2When dealing with young people’s MDMs, it can be observed that the cell’s glycolysis and oxidative phosphorylation capabilities are significantly reduced, which means that the power of the two most important engines of immune cells has gone wrong. After treatment with inhibitors targeting the PGE2 receptor EP2, the efficiency of the two metabolic pathways quickly recovered significantly.

In experiments on elderly mice, the research team re-verified the previous findings: knocking out the EP2 receptor in mouse myeloid cells(EP2 levels decreased After 50%), the macrophages of aging mice are relatively healthier, and they show better spatial memory in the Barnes maze experiment, suggesting the effect of reversing the aging brain.

Knockout of EP2 directly affects the number of mitochondria and abnormal ratio of macrophages

Next, the research team dug into the mechanism by which the PGE2-EP2 pathway affects the energy metabolism of macrophages, which is the mechanism mentioned at the beginning of the article: this pathway will promote the macrophages to transfer glucose It is converted into glycogen and then stored in the cell, reducing the level of glucose flow in the cell and affecting the energy supply of the cell.

In fact, this metabolic reprogramming of senescent macrophages is a routine operation of immune cells. For example, dendritic cells can store glycogen, and then use these “strategic reserves” when an inflammatory response is needed, such as infection. But in aging macrophages, glycogen is really completely sealed, at least not used during the aging process.

As for why macrophages store glycogen, this study did not give an answer, but microglia, which functions similarly to macrophages in the brain, may also have such characteristics. Studies have shown that a TREM2 mutation that can cause abnormal microglia metabolism is associated with a significant increase in the risk of AD.[4].

The last step of the research is to evaluate whether the use of drugs to inhibit EP2 can reverse the aging of the brain in mice, and the result is really a bit unexpected: No matter it is used to cross the blood-brain barrier, it acts on the inhibition of microglia. Or use inhibitors that can only affect macrophages outside the brain. The brains of mice are showing a trend of youthfulness.

The effect of inhibiting EP2 is that the brain and cells “return to youth”

The editorial issued by “Nature” stated that if the specific mechanism that inhibits the EP2 receptor of peripheral macrophages can be found to make the brains of aging mice rejuvenated, it is expected that the research results will be quickly transferred to the clinic.

Professor Katrin Andreasson, the corresponding author of this study, also pointed out that precise inhibition of EP2 “may be very difficult”. The two EP2 inhibitors used in the study are still in the development stage, and the direct use of aspirin is too broad. There may be side effects, so we need to continue to work [5].

For scientific research, we always discover new problems while solving problems. Singularity Cake believes that in the future we will definitely see new drugs developed based on this paper. Reversing the aging brain, who doesn’t want such a medicine? The research power is directly full.

Reference materials:

1.Minhas P S, Latif-Hernandez A, Mcreynolds M R, et al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing[J]. Nature, 2021.

2.Montine TJ, Sidell KR, Crews BC, et al. Elevated CSF prostaglandin E2 levels in patients with probable AD[J]. Neurology, 1999, 53(7): 1495-1495.

3.Etminan M, Gill S, Samii A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: systematic review and meta-analysis of observational studies[J ]. BMJ, 2003, 327(7407): 128.

4.Ulland TK, Song WM, Huang SCC, et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease[J]. Cell, 2017, 170(4): 649- 663. e13.


This article is from WeChat official account:Geekheal (ID: geekheal_com), author: Tan Shuo