Cell Stem Cell | Anti-aging as early as possible—Mature brains have already appeared with molecular aging characteristics of neural stem cells

Author | Qi In recent years, the anti-aging phenomenon of young people has become more and more common.

However, since it is impossible to determine when and which cells begin to undergo cell aging, the progress of research on slowing down or reversing the decline in tissue function is hindered.

Compared with young animals, the number, proliferation and differentiation of neural stem cells (NSC), and the survival rate of newborn neurons in elderly animals are reduced, and they are characterized by molecular aging [1].

Interestingly, in the early mature brains of rodents and in the middle-aged human hippocampus, neurogenesis has already experienced loss of neurogenesis, accompanied by epigenetic loss of DNA demethylation [2], suggesting that the early stages of aging may be the first Molecular aging has occurred.

However, the internal drive mechanism is unclear.

One theory is that the limited self-renewal ability of the NSC pool in the hippocampus, and pathological conditions that force neurogenesis can lead to premature depletion of neural stem cells; another theory is that neurogenesis is due to the long-term resting state of neural stem cells.
And decline [3].

Although neural stem cells as a group have clearly undergone age-related early changes, it is not clear when and how specific neural stem cell subgroups begin to become dysfunctional.

Recently, Michael A.
Bonaguidi’s team from the University of Southern California published an article titled "Early stem cell aging in the mature brain" in Cell Stem Cell.
This study uses a single-cell method to study the initial damage to adults.
The cellular and molecular mechanisms of neurogenesis confirmed that the NSCs subpopulation experienced a non-synchronous decline and exhibited early molecular aging.
Therefore, targeting these cellular aging mechanisms in the middle-aged brain can partially overcome age-related neural stem cell functions obstacle.First, consistent with previous studies, the authors found that the number of neural stem cells decreases over time, while the frequency of differentiation of the remaining neural stem cells at the population level is not high.

Subsequently, the authors performed extensive in vivo single-cell clone lineage tracking and computational modeling on Nestin-CreERT2 (Nestin#) and Ascl1-CreERT2 (Ascl1#) mice under physiological conditions of 2, 6, and 12 months.
The results It shows that in young, mature and middle-aged hippocampus, Nestin#-NSCs clones maintain better than Ascl1#-NSCs clones.
NSCs subgroups of multiple ages have consistent short-lived and long-lived characteristics, while Nestin#- NSCs represent long-term NSCs (LT-NSCs) and can be used to determine the mechanism that mediates the initial loss of stem cell homeostasis in the mature brain.

When the rate of self-renewal of NSCs is balanced with the rate of differentiation, NSCs are in a homeostasis state.

So what behaviors of stem cells cause the loss of homeostasis of NSCs? The authors performed cloning, cell cycle dynamics and cell fate analysis on Nestin#-NSCs of 2, 6, and 12 months old mice, and followed them for 4 months.

Interestingly, the author found that Nestin#-NSCs showed a significant increase in quiescence in the young hippocampus, and entered a deeper quiescence state in the mature brain, thereby losing homeostasis.

In the 2-month-old young hippocampus, Nestin#-NSCs will make asymmetric fate choices for neurons and astrocytes, and after gradually maturing and losing homeostasis, they will turn to symmetrical cell fate choices, which will further Inhibit neurogenesis.

In order to reveal the molecular mechanism of the gradual resting of NSCs, the authors used single-cell sequencing to try to determine the transcriptomic changes associated with the deep resting of NSCs.

Compared with 2-month-old mice, 493 up-regulated genes and 576 down-regulated genes were differentially expressed in 4.
5-month-old resting NSCs. It is noteworthy that the changes in molecular markers that drive cell aging, such as DNA damage, histone demethylase dysregulation, changes in metabolism and transcription, decreased cell cycle entry, and changes in cell fate deviation, are all found in quiescent NSCs.
The detection indicates that the functional changes of deep neural stem cells in the resting phase are related to the early molecular aging of neural stem cells in the mature hippocampus.

So now that it has been discovered that neural stem cells have experienced early molecular aging in the mature brain, can they use this as a target to overcome the dysfunction of elderly neural stem cells? To this end, the author first focused on Abl1, Abl2, Igf1, Lef1, Per2, and Nup62, which are the central genes that are most relevant to age-related changes in NSC function.
Among them, special attention is paid to Abl1, whose role in the biology of NSCs is unknown.

The author tried to use imatinib to inhibit Abl1 as a strategy to target the aging of NSC cells, so imatinib was injected into the hippocampus of 10-month-old mice, and the effects on neural stem cells were tested on 6 and 28 days, respectively.

Interestingly, at 6 days, imatinib can restore the percentage of proliferating neural stem cells in the middle-aged hippocampus to a young level without changing the number of neural stem cells; and at 28 days, the neural stem cell pool was not overactive.
Exhausted prematurely, but became more static.

In summary, this study showed that short-term and long-term NSCs exhibit asynchronous depletion through clone tracing, and single-cell transcriptome analysis of deep neural stem cells in the resting phase revealed molecular aging characteristics in mature brains.

Although imatinib has been shown to regulate neural stem cell dynamics, it can also inhibit c-Kit and PDGRF tyrosine kinases while reducing Abl1.
In the future, it is necessary to further confirm the regulation of imatinib.
Molecular targets.

In short, understanding the key mechanisms that drive the molecular aging of NSCs will help create new directions for promoting age-related regenerative treatments.

Reprinting Instructions [Original Articles] BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt.

BioArt reserves all statutory rights and offenders must be investigated.

Original link: https://doi.
org/10.
1016/j.
stem.
2021.
03.
018 Plate maker: Qijiang References 1.
Kirschen, GW, Ge, S.
, and Snyder, JS (2019).
Young at heart: Insights into hippocampal neurogenesis in the aged brain.
Behav.
Brain Res.
369, 111934.
2.
Gontier, G.
, Iyer, M.
, Shea, JM, Bieri, G.
, Wheatley, EG, Ramalho-Santos, M.
, and Villeda , SA (2018).
Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain.
Cell Rep.
22, 1974–1981.
3.
Bonaguidi, MA, Wheeler, MA, Shapiro, JS, Stadel, RP, Sun, GJ, Ming, GL, and Song, H.
(2011).
In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics.
Cell 145, 1142–1155.