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Ageing is an irreversible change that everyone has to experience.
Therefore, the research enthusiasm of researchers for it has remained unchanged.
How to still have young brain power and athletic ability after aging is a hot topic
.
It is well known that immune cells, especially macrophages, play a major role in nerve pruning and structural remodeling [1]
.
However, researchers in Germany recently discovered that cytotoxic T cells also play a non-negligible role in this process: they enhance the degeneration of nerve axons and are accomplices in the decline of cognitive and motor abilities in the process of getting older
.
The research paper was published in the journal "Nature·Aging" [2]
.
The research team focused on the optic nerve
.
Because with age, the optic nerve in the central nervous system has obvious damage-compared with adult (12 months) mice, elderly (24 months) mice have more protection around the optic nerve axons The fragments of the myelin structure of the nerve, the number of axons are reduced, the inner layer of the retina becomes thinner, and the exercise ability and memory of old mice are weakened
.
Researchers believe that neuroinflammation in the central nervous system may be one of the reasons for regulating all this
.
They found that there is a significant increase in CD8+ T cells in the aging brain tissue.
These cells mainly play a cytotoxic killing effect in the work of the immune system, that is, inject toxins into the cells to kill viruses or bacteria infected.
In contrast, there are not so many CD4+ T cells
.
They observed that in the brains of old mice, CD8+ T cells increased significantly in the vicinity of the white matter where the axons were concentrated, but not in the gray matter where the neuronal cell bodies were located, and some CD8+ T cells were adjacent to the axons with abnormal structures.
, People can't help linking this behavior of immune cells to the destruction and degeneration of the myelin sheath of nerve axons
.
Removal of T cells in the brains of old mice resulted in less destruction of myelin and axons, and the mice’s exercise ability and memory were restored.
In order to confirm the function of T cells in them, the researchers removed the T cells in the mice.
Surprisingly, the destruction of axons and myelin sheaths caused by aging has been weakened in the brains of these mice.
Compared with wild-type mice, the exercise capacity of the old mice lacking T cells is as good as that of wild type mice.
Memory has become better, which shows that T cells do have a certain destructive effect in the brain of old mice
.
In order to better confirm the functions of these T cells, the author extracted CD8+ T cells from the brains of aged and adult mice and performed single-cell sequencing, and found that there were mainly five groups of cells
.
Among them, the number increases significantly with age.
They express the immune checkpoint molecules LAG3 and PD-1, which represent the continuous activation of T cells; this activation may be caused by self-antigens
.
In addition, the cytotoxic effector molecule granzyme B expressed by CD8+ T cells increased
.
In order to better understand the role of CD8+ T cells in the aging process of the brain, the authors reinfused bone marrow to middle-aged and elderly adaptive immune cell-deficient mice to rebuild their immune systems
.
Compared with the infusion of bone marrow lacking CD8+T, the infusion of normal bone marrow leads to obvious brain aging and axonal damage: when there is no CD8+T in the brain, its damage is significantly reduced; the inner layer of the retina becomes thinner, The loss of retinal ganglion cells and the damage of exercise ability, which are caused by old age, are also reduced
.
The infusion of CD8+ T cells deficient in granzyme B or not recognizing self-antigens can also better protect the brain nerves of old mice
.
From this result, when the number of CD8+ T cells is reduced, cannot be activated, or the expression of cytotoxic effector molecules is reduced, the damage to the brain caused by aging is significantly reduced, and the exercise ability caused by aging is also reduced to a certain extent.
Recovery
.
CD8+T loss, CD8+T does not express granzyme B, and CD8+T does not recognize autoantigens.
The brain damage of old mice is reduced.
Since the weakening of CD8+T cell function reduces the brain damage caused by aging, it is more Will strong CD8+ T cells lead to a more serious aging phenotype? The researchers used lipopolysaccharide (LPS) intraperitoneal injection to stimulate the systemic immune response.
After 4 weeks, the CD8+ T cells and CD4+ T cells in the mouse brain increased
.
This accumulation has no effect on middle-aged mice; but in older mice, enhanced CD8+ T cell recruitment is positively correlated with more severe axon damage, thinning of the retina, and neuron loss, and their vision is also significantly changed.
It is bad; this change is not observed in old mice lacking CD8+ T cells
.
LPS enhances the damage of CD8+T to the aging brain.
In short, we concluded that CD8+T cells drive the axon degeneration of the central nervous system in the elderly
.
The effect mechanism involved is dependent on the cytotoxic serine protease granzyme B, and occurs in an antigen and TCR dependent manner
.
CD8+ T cells of the central nervous system are important effectors of aging-related neurodegeneration and dysfunction, and this harmful effect is further enhanced in the case of systemic inflammation
.
Finally, the author observed the brain tissue samples of the elderly without neurological diseases, and observed the accumulation of CD8+ T cells in the perivascular and white matter of the elderly.
LAG3+CD8+ T cells, which account for the main proportion of T cells, increased, and some expressed granzyme B.
And concentrated near the damaged axon
.
The cerebral cortex (gray matter) has no such changes; at the same time, there is no significant increase in CD4+ T cells in the brain
.
There are more LAG3+CD8+ T cells in the brain samples of the elderly, and they are close to the myelin sheath.
The study found that CD8+ T cells began to accumulate in the brain after 18 months of mice, possibly by destroying the axon myelin sheath.
The method resulted in the damage of axons, and finally resulted in the deterioration of the exercise ability and memory of the old mice
.
There are few reports on the function of CD8+T before it affects the central nervous system, but this article describes its mechanism of damage to the aging brain by destroying axons and myelin
.
The article can provide an explanation for the impact of brain function in immunotherapy; it can explain the impairment of exercise capacity and vision caused by aging; be aware that the naturally occurring systemic inflammation may lead to stronger brain aging in the elderly And damage
.
References: 1.
Grabert K, Michoel T, Karavolos MH, Clohisey S, Baillie JK, Stevens MP, et al.
Microglial brain region-dependent diversity and selective regional sensitivities to aging.
Nat Neurosci 2016; 19(3):504- 516.
2.
Groh, J.
, Knöpper, K.
, Arampatzi, P.
et al.
Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline.
Nat Aging 1, 357–367 (2021) .
https://doi.
org/10.
1038/s43587-021-00049-z Chief Editor | Dai Siyu
Therefore, the research enthusiasm of researchers for it has remained unchanged.
How to still have young brain power and athletic ability after aging is a hot topic
.
It is well known that immune cells, especially macrophages, play a major role in nerve pruning and structural remodeling [1]
.
However, researchers in Germany recently discovered that cytotoxic T cells also play a non-negligible role in this process: they enhance the degeneration of nerve axons and are accomplices in the decline of cognitive and motor abilities in the process of getting older
.
The research paper was published in the journal "Nature·Aging" [2]
.
The research team focused on the optic nerve
.
Because with age, the optic nerve in the central nervous system has obvious damage-compared with adult (12 months) mice, elderly (24 months) mice have more protection around the optic nerve axons The fragments of the myelin structure of the nerve, the number of axons are reduced, the inner layer of the retina becomes thinner, and the exercise ability and memory of old mice are weakened
.
Researchers believe that neuroinflammation in the central nervous system may be one of the reasons for regulating all this
.
They found that there is a significant increase in CD8+ T cells in the aging brain tissue.
These cells mainly play a cytotoxic killing effect in the work of the immune system, that is, inject toxins into the cells to kill viruses or bacteria infected.
In contrast, there are not so many CD4+ T cells
.
They observed that in the brains of old mice, CD8+ T cells increased significantly in the vicinity of the white matter where the axons were concentrated, but not in the gray matter where the neuronal cell bodies were located, and some CD8+ T cells were adjacent to the axons with abnormal structures.
, People can't help linking this behavior of immune cells to the destruction and degeneration of the myelin sheath of nerve axons
.
Removal of T cells in the brains of old mice resulted in less destruction of myelin and axons, and the mice’s exercise ability and memory were restored.
In order to confirm the function of T cells in them, the researchers removed the T cells in the mice.
Surprisingly, the destruction of axons and myelin sheaths caused by aging has been weakened in the brains of these mice.
Compared with wild-type mice, the exercise capacity of the old mice lacking T cells is as good as that of wild type mice.
Memory has become better, which shows that T cells do have a certain destructive effect in the brain of old mice
.
In order to better confirm the functions of these T cells, the author extracted CD8+ T cells from the brains of aged and adult mice and performed single-cell sequencing, and found that there were mainly five groups of cells
.
Among them, the number increases significantly with age.
They express the immune checkpoint molecules LAG3 and PD-1, which represent the continuous activation of T cells; this activation may be caused by self-antigens
.
In addition, the cytotoxic effector molecule granzyme B expressed by CD8+ T cells increased
.
In order to better understand the role of CD8+ T cells in the aging process of the brain, the authors reinfused bone marrow to middle-aged and elderly adaptive immune cell-deficient mice to rebuild their immune systems
.
Compared with the infusion of bone marrow lacking CD8+T, the infusion of normal bone marrow leads to obvious brain aging and axonal damage: when there is no CD8+T in the brain, its damage is significantly reduced; the inner layer of the retina becomes thinner, The loss of retinal ganglion cells and the damage of exercise ability, which are caused by old age, are also reduced
.
The infusion of CD8+ T cells deficient in granzyme B or not recognizing self-antigens can also better protect the brain nerves of old mice
.
From this result, when the number of CD8+ T cells is reduced, cannot be activated, or the expression of cytotoxic effector molecules is reduced, the damage to the brain caused by aging is significantly reduced, and the exercise ability caused by aging is also reduced to a certain extent.
Recovery
.
CD8+T loss, CD8+T does not express granzyme B, and CD8+T does not recognize autoantigens.
The brain damage of old mice is reduced.
Since the weakening of CD8+T cell function reduces the brain damage caused by aging, it is more Will strong CD8+ T cells lead to a more serious aging phenotype? The researchers used lipopolysaccharide (LPS) intraperitoneal injection to stimulate the systemic immune response.
After 4 weeks, the CD8+ T cells and CD4+ T cells in the mouse brain increased
.
This accumulation has no effect on middle-aged mice; but in older mice, enhanced CD8+ T cell recruitment is positively correlated with more severe axon damage, thinning of the retina, and neuron loss, and their vision is also significantly changed.
It is bad; this change is not observed in old mice lacking CD8+ T cells
.
LPS enhances the damage of CD8+T to the aging brain.
In short, we concluded that CD8+T cells drive the axon degeneration of the central nervous system in the elderly
.
The effect mechanism involved is dependent on the cytotoxic serine protease granzyme B, and occurs in an antigen and TCR dependent manner
.
CD8+ T cells of the central nervous system are important effectors of aging-related neurodegeneration and dysfunction, and this harmful effect is further enhanced in the case of systemic inflammation
.
Finally, the author observed the brain tissue samples of the elderly without neurological diseases, and observed the accumulation of CD8+ T cells in the perivascular and white matter of the elderly.
LAG3+CD8+ T cells, which account for the main proportion of T cells, increased, and some expressed granzyme B.
And concentrated near the damaged axon
.
The cerebral cortex (gray matter) has no such changes; at the same time, there is no significant increase in CD4+ T cells in the brain
.
There are more LAG3+CD8+ T cells in the brain samples of the elderly, and they are close to the myelin sheath.
The study found that CD8+ T cells began to accumulate in the brain after 18 months of mice, possibly by destroying the axon myelin sheath.
The method resulted in the damage of axons, and finally resulted in the deterioration of the exercise ability and memory of the old mice
.
There are few reports on the function of CD8+T before it affects the central nervous system, but this article describes its mechanism of damage to the aging brain by destroying axons and myelin
.
The article can provide an explanation for the impact of brain function in immunotherapy; it can explain the impairment of exercise capacity and vision caused by aging; be aware that the naturally occurring systemic inflammation may lead to stronger brain aging in the elderly And damage
.
References: 1.
Grabert K, Michoel T, Karavolos MH, Clohisey S, Baillie JK, Stevens MP, et al.
Microglial brain region-dependent diversity and selective regional sensitivities to aging.
Nat Neurosci 2016; 19(3):504- 516.
2.
Groh, J.
, Knöpper, K.
, Arampatzi, P.
et al.
Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline.
Nat Aging 1, 357–367 (2021) .
https://doi.
org/10.
1038/s43587-021-00049-z Chief Editor | Dai Siyu
