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Original author: Jonas J.
Neher's research found that a type of immune cell called macrophages shuts down its main metabolic pathway during aging; and restoring the metabolism of these cells can alleviate the age-related cognitive decline in mice.
Macrophages (a type of immune cell) are found in almost all tissues and are indispensable for maintaining organ health.
At the same time, they are also an important part of the first line of defense against pathogens.
When macrophages are activated, their energy requirements will increase sharply, so they will rebalance or enhance the two main energy-supplying metabolic pathways (glycolysis and oxidative phosphorylation) to quickly initiate an effective immune response [1].
Minhas et al.
[2] reported in a paper published in the journal Nature that macrophages shut down these metabolic pathways during the aging process, severely impairing the function of macrophages and affecting brain health.
The significance of this research is not only how to keep the brain healthy during the aging process, but also has enlightening effects on diseases such as Alzheimer's disease or sepsis.
In these diseases, similar macrophage maladaptation may be very common.
With age, mild chronic inflammation appears in most people's body [3].
Prostaglandin E2 (PGE2) is an inflammatory signaling protein, and its level will increase significantly during the aging process [4] and neurodegenerative diseases [5].
The original intention of Minhas et al.
's study is to explore whether PGE2 can cause senescence-related changes in macrophages.
They found that whether in humans or mice, the level of PGE2 in macrophages increased significantly during the aging process-in the brain and in the periphery.
Increased levels of PGE2 activate the intracellular PGE2 receptor protein EP2, which in turn inhibits oxidative phosphorylation and glycolysis.
Insufficient energy supply not only limits the beneficial functions of macrophages, but also promotes the inflammatory response.
In order to determine whether these changes will cause age-related cognitive dysfunction, the researchers adopted two methods.
The first is to select specific mice as the research object.
These mice have significant levels of EP2 receptors in macrophages.
Decrease; the second method is to treat mice with EP2 receptor inhibitors.
They found that no matter which method is used, inhibition of EP2 receptor function can restore macrophage metabolism to a young level, reduce peripheral and central inflammation, and thereby alleviate cognitive decline (Figure 1).
These findings indicate that during aging, macrophage dysfunction can affect brain health, and reversing the "metabolic shutdown" of cells can restore normal cell function (at least in mice).
Figure 1 | Reversing the decrease in metabolism of senescent macrophages.
Immune cells called macrophages are found throughout the periphery and the center, and in the brain they are called microglia.
a, Minhas et al.
[2] found that peripheral macrophages and microglia will produce more prostaglandin E2 (PGE2) during aging.
After PGE2 binds to the EP2 receptor on the cell membrane, it activates specific signaling pathways and leads to metabolic dysfunction in the cell, resulting in chronic inflammation and cognitive decline throughout the body.
b.
The researchers used two methods to inhibit EP2 receptors.
The first is to reduce the level of EP2 in macrophages and microglia through genetic methods; the second is to inhibit the receptor from a pharmacological point of view, but only inhibit the peripheral EP2 receptor.
No matter which method is used, inhibition of EP2 can significantly improve the metabolic function of peripheral macrophages and microglia, reduce inflammation, and restore cognitive function.
However, the reasons behind why peripheral EP2 function can also cause changes in the metabolic function of microglia are unclear (dashed arrow).
Minhas and colleagues further studied the metabolic state of macrophages during aging.
They found that such macrophages are more inclined to store energy in the form of glycogen (a polymer of glucose with a larger molecular weight), rather than using glucose to produce energy through glycolysis or oxidative phosphorylation.
Although glycogen is a common form of energy reserves, aging macrophages do not seem to use these reserves, even though they are in a severely energy-deficient state.
Why aging macrophages store extra glycogen is not yet clear, but previous studies have shown that dendritic cells (a related immune cell) use their glycogen stores to power their early inflammatory response [6].
We may infer that the increased glycogen storage of aging macrophages can help them produce a stronger immune response during the activation of acute inflammation.
Supporting this inference is another well-known fact that microglia (macrophages in the brain) become more "irritable" after aging, that is, respond more strongly to inflammatory stimuli [7].
Minhas and his team did not directly analyze whether the increase in glycogen storage is the reason behind the "emotional changes" in microglia, but this possibility is clearly worthy of further exploration, because there is evidence that inflammation in the brain of the elderly may cause Neurodegenerative diseases [7].
Another noteworthy issue is that previous studies have suggested that the metabolic dysfunction of microglia may be related to the occurrence and development of brain diseases, especially Alzheimer's disease.
Compared with normal people, people with mutations in the microglial cell receptor protein TREM2 have an increased risk of Alzheimer's disease several times.
In mice, the lack of TREM2 receptors can cause microglia metabolism disorders, and the pathological manifestations of Alzheimer's disease will also be aggravated [8].
In addition, animal experiments have also shown that long-term exposure of microglia to aggregated amyloid β (a sign of Alzheimer's disease) environment will affect the oxidative phosphorylation and glycolysis of cells [9].
In both cases, restoring the metabolic function of microglia can improve the pathological manifestations of Alzheimer's disease in mice to a certain extent.
In sepsis (excessive inflammation caused by infection), PGE2 levels will also increase [9], and patients may also experience long-term cognitive impairment [7].
In this case, macrophages enter a state called "immune paralysis", the main characteristics of this state include oxidative phosphorylation and glycolysis pathways are inhibited [1,10].
Therefore, in sepsis and aging (neurodegenerative diseases), the closure of macrophage metabolic pathways may be due to excessive or chronic inflammatory stimulation.
From an evolutionary point of view, this may be a beneficial adaptation, which can protect the body from damage caused by an overactive immune response.
But in the process of individual aging, the closure of this metabolic pathway seems to make the brain prone to dysfunction and even degenerative diseases.
In these different situations, whether the immune status of macrophages is indeed similar remains to be further studied.
Another intriguing finding of the study by Minhas and colleagues is that in aging mice, even inhibiting peripheral EP2 receptors (using inhibitors that cannot enter the central nervous system) can reverse brain inflammation and restore cognitive function in mice.
(figure 1).
Previous studies also have similar results.
Immune signals outside the brain can also affect microglia [11].
Stimulating immune cells in the non-central system can partially restore the metabolism and function of peripheral macrophages after sepsis [10], It has a similar effect on microglia in a mouse model of Alzheimer's disease [9].
All the growing evidence shows that in mice, macrophages can still respond to immune stimulation, even in disease and aging conditions.
In the future, we still have many problems to be solved-can this plasticity of macrophages survive to the end of the much longer lifespan of humans? What role does the PGE2–EP2 pathway play in human brain aging and disease? What is the immune signal that initially induces the closure of the metabolic pathways of microglia? What is the "elixir" that makes the microglia in aging animals "rejuvenate"? Finding these key immune signals may help us develop new treatments for many diseases.
The original article was published under the title Reversal of immune-cell shutdown protects the ageing brain in the News and Views section of Nature on January 20, 2021 © naturedoi: 10.
1038/d41586-021-00063-6 In addition to being thin, the exercise of reading related articles with text or pictures can also promote the bone marrow to "make" immune cells! The aging clock may be reset.
Can cells really "rejuvenate"? Always have a stomachache after eating? It may be that the immune system "tagged the wrong person" Copyright notice: This article was translated by Springer Nature Shanghai Office. The content in Chinese is for reference only, and the original English version shall prevail for all content.
Neher's research found that a type of immune cell called macrophages shuts down its main metabolic pathway during aging; and restoring the metabolism of these cells can alleviate the age-related cognitive decline in mice.
Macrophages (a type of immune cell) are found in almost all tissues and are indispensable for maintaining organ health.
At the same time, they are also an important part of the first line of defense against pathogens.
When macrophages are activated, their energy requirements will increase sharply, so they will rebalance or enhance the two main energy-supplying metabolic pathways (glycolysis and oxidative phosphorylation) to quickly initiate an effective immune response [1].
Minhas et al.
[2] reported in a paper published in the journal Nature that macrophages shut down these metabolic pathways during the aging process, severely impairing the function of macrophages and affecting brain health.
The significance of this research is not only how to keep the brain healthy during the aging process, but also has enlightening effects on diseases such as Alzheimer's disease or sepsis.
In these diseases, similar macrophage maladaptation may be very common.
With age, mild chronic inflammation appears in most people's body [3].
Prostaglandin E2 (PGE2) is an inflammatory signaling protein, and its level will increase significantly during the aging process [4] and neurodegenerative diseases [5].
The original intention of Minhas et al.
's study is to explore whether PGE2 can cause senescence-related changes in macrophages.
They found that whether in humans or mice, the level of PGE2 in macrophages increased significantly during the aging process-in the brain and in the periphery.
Increased levels of PGE2 activate the intracellular PGE2 receptor protein EP2, which in turn inhibits oxidative phosphorylation and glycolysis.
Insufficient energy supply not only limits the beneficial functions of macrophages, but also promotes the inflammatory response.
In order to determine whether these changes will cause age-related cognitive dysfunction, the researchers adopted two methods.
The first is to select specific mice as the research object.
These mice have significant levels of EP2 receptors in macrophages.
Decrease; the second method is to treat mice with EP2 receptor inhibitors.
They found that no matter which method is used, inhibition of EP2 receptor function can restore macrophage metabolism to a young level, reduce peripheral and central inflammation, and thereby alleviate cognitive decline (Figure 1).
These findings indicate that during aging, macrophage dysfunction can affect brain health, and reversing the "metabolic shutdown" of cells can restore normal cell function (at least in mice).
Figure 1 | Reversing the decrease in metabolism of senescent macrophages.
Immune cells called macrophages are found throughout the periphery and the center, and in the brain they are called microglia.
a, Minhas et al.
[2] found that peripheral macrophages and microglia will produce more prostaglandin E2 (PGE2) during aging.
After PGE2 binds to the EP2 receptor on the cell membrane, it activates specific signaling pathways and leads to metabolic dysfunction in the cell, resulting in chronic inflammation and cognitive decline throughout the body.
b.
The researchers used two methods to inhibit EP2 receptors.
The first is to reduce the level of EP2 in macrophages and microglia through genetic methods; the second is to inhibit the receptor from a pharmacological point of view, but only inhibit the peripheral EP2 receptor.
No matter which method is used, inhibition of EP2 can significantly improve the metabolic function of peripheral macrophages and microglia, reduce inflammation, and restore cognitive function.
However, the reasons behind why peripheral EP2 function can also cause changes in the metabolic function of microglia are unclear (dashed arrow).
Minhas and colleagues further studied the metabolic state of macrophages during aging.
They found that such macrophages are more inclined to store energy in the form of glycogen (a polymer of glucose with a larger molecular weight), rather than using glucose to produce energy through glycolysis or oxidative phosphorylation.
Although glycogen is a common form of energy reserves, aging macrophages do not seem to use these reserves, even though they are in a severely energy-deficient state.
Why aging macrophages store extra glycogen is not yet clear, but previous studies have shown that dendritic cells (a related immune cell) use their glycogen stores to power their early inflammatory response [6].
We may infer that the increased glycogen storage of aging macrophages can help them produce a stronger immune response during the activation of acute inflammation.
Supporting this inference is another well-known fact that microglia (macrophages in the brain) become more "irritable" after aging, that is, respond more strongly to inflammatory stimuli [7].
Minhas and his team did not directly analyze whether the increase in glycogen storage is the reason behind the "emotional changes" in microglia, but this possibility is clearly worthy of further exploration, because there is evidence that inflammation in the brain of the elderly may cause Neurodegenerative diseases [7].
Another noteworthy issue is that previous studies have suggested that the metabolic dysfunction of microglia may be related to the occurrence and development of brain diseases, especially Alzheimer's disease.
Compared with normal people, people with mutations in the microglial cell receptor protein TREM2 have an increased risk of Alzheimer's disease several times.
In mice, the lack of TREM2 receptors can cause microglia metabolism disorders, and the pathological manifestations of Alzheimer's disease will also be aggravated [8].
In addition, animal experiments have also shown that long-term exposure of microglia to aggregated amyloid β (a sign of Alzheimer's disease) environment will affect the oxidative phosphorylation and glycolysis of cells [9].
In both cases, restoring the metabolic function of microglia can improve the pathological manifestations of Alzheimer's disease in mice to a certain extent.
In sepsis (excessive inflammation caused by infection), PGE2 levels will also increase [9], and patients may also experience long-term cognitive impairment [7].
In this case, macrophages enter a state called "immune paralysis", the main characteristics of this state include oxidative phosphorylation and glycolysis pathways are inhibited [1,10].
Therefore, in sepsis and aging (neurodegenerative diseases), the closure of macrophage metabolic pathways may be due to excessive or chronic inflammatory stimulation.
From an evolutionary point of view, this may be a beneficial adaptation, which can protect the body from damage caused by an overactive immune response.
But in the process of individual aging, the closure of this metabolic pathway seems to make the brain prone to dysfunction and even degenerative diseases.
In these different situations, whether the immune status of macrophages is indeed similar remains to be further studied.
Another intriguing finding of the study by Minhas and colleagues is that in aging mice, even inhibiting peripheral EP2 receptors (using inhibitors that cannot enter the central nervous system) can reverse brain inflammation and restore cognitive function in mice.
(figure 1).
Previous studies also have similar results.
Immune signals outside the brain can also affect microglia [11].
Stimulating immune cells in the non-central system can partially restore the metabolism and function of peripheral macrophages after sepsis [10], It has a similar effect on microglia in a mouse model of Alzheimer's disease [9].
All the growing evidence shows that in mice, macrophages can still respond to immune stimulation, even in disease and aging conditions.
In the future, we still have many problems to be solved-can this plasticity of macrophages survive to the end of the much longer lifespan of humans? What role does the PGE2–EP2 pathway play in human brain aging and disease? What is the immune signal that initially induces the closure of the metabolic pathways of microglia? What is the "elixir" that makes the microglia in aging animals "rejuvenate"? Finding these key immune signals may help us develop new treatments for many diseases.
The original article was published under the title Reversal of immune-cell shutdown protects the ageing brain in the News and Views section of Nature on January 20, 2021 © naturedoi: 10.
1038/d41586-021-00063-6 In addition to being thin, the exercise of reading related articles with text or pictures can also promote the bone marrow to "make" immune cells! The aging clock may be reset.
Can cells really "rejuvenate"? Always have a stomachache after eating? It may be that the immune system "tagged the wrong person" Copyright notice: This article was translated by Springer Nature Shanghai Office. The content in Chinese is for reference only, and the original English version shall prevail for all content.
