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Responsible editor | Various stress environments such as radiation, oxidative stress, and telomere shortening induce cells to present an irreversible cell cycle arrest state, accompanied by high expression of p16 and p21 genes, that is, senescent cells (Senescent cells) [1]
.
The accumulation of senescent cells and the senescence-associated secretory phenotype (SASP) are the hallmarks of body aging, and they are also an important mechanism for the occurrence of senescence and its related chronic diseases
.
In October 2021, Xu Ming's research group at the University of Connecticut reported a new p21-Cre transgenic mouse model for tracking and regulating p21high senescent cells in the body, and found that there are p21high senescent cells in various organs of old mice.
And the specific elimination of the senescent cells can effectively delay the body's aging (see BioArt report: Nature Aging | Xu Ming's team established a p21-Cre mouse model to reveal the role of p21high cells in aging)
.
In addition, the team also detected obvious p21high cell aggregation in obese mice fed high-fat [2]
.
Insulin resistance is one of the main characteristics of type 2 diabetes, and obesity is the key cause of insulin resistance and type 2 diabetes
.
Regarding whether p21high senescent cells are involved in the occurrence of obesity-related insulin resistance, and whether p21high senescent cells can be targeted by drugs to improve insulin resistance and diabetes, these two questions remain to be answered
.
On November 22, 2021, Xu Ming’s team published another long article Targeting p21Cip1-highly-expressing cells in adipose tissue alleviates insulin resistance in obesity in Cell Metabolism, revealing that the accumulation of p21high senescent cells in adipose tissue alleviates insulin resistance in obesity is the cause of insulin resistance.
The drug combination of dasatinib and quercetin can effectively eliminate p21high cells in human adipose tissue and improve the metabolic function of fat transplanted mice
.
This study provides an important basis for using p21high cells as a new therapeutic target for reducing insulin resistance
.
The researchers first used single-cell transcriptome sequencing and found that the adipose tissue of obese mice fed high-fat for two months had a higher level of p21high cells, and they were mainly concentrated in adipose precursor cells, endothelial cells and macrophages; and At the same time, no obvious p16high cells were detected
.
They used the p21-Cre transgenic mouse model constructed earlier and combined with flow cytometry to further confirm the distribution of p21high senescent cells in the adipose tissue of obese mice
.
P21high senescent cells and p16high senescent cells are two common types of senescent cells
.
The researchers then verified the results of single-cell sequencing at the gene and protein levels respectively, that is, the adipose tissue of obese mice fed short-term high-fat diet mainly had accumulation of p21high senescent cells instead of p16high senescent cells
.
Obesity causes adipose tissue expansion and dysfunction, which ultimately leads to insulin resistance and type 2 diabetes
.
To explore whether p21high senescent cells are involved in regulating obesity-related insulin resistance, the researchers crossed p21-Cre mice with floxed DTA (diphtheria toxin A fragment) mice to specifically eliminate p21high senescent cells in the body
.
With the elimination of these cells, the glucose tolerance and insulin sensitivity of obese mice can be significantly improved
.
In addition, the aging-related β-galactosidase activity and telomere DNA damage in the adipose tissue of obese mice after clearing p21high senescent cells were significantly reduced, the cell proliferation ability was effectively restored, and the expression of SASP was also significantly reduced
.
However, the body weight, body fat rate, average daily food intake and activity level of mice did not change significantly, indicating that the elimination of p21high senescent cells mainly works by reducing the degree of tissue aging rather than eating activities in mice
.
In order to confirm the tissue source of p21high senescent cells that cause insulin resistance in obese mice, the researchers first used immunofluorescence and bioluminescence imaging techniques to observe different tissues of obese mice.
They found that p21high senescent cells were mainly distributed in visceral adipose tissue, while the liver , Pancreas, muscle and other tissues are not obvious
.
Next, the researchers transplanted the visceral fat from obese mice to normal mice.
The results showed that the fat transplantation can cause insulin resistance in the recipient mice; and the p21high senescent cells that remove the visceral fat from the donor body can significantly improve the fat transplantation.
The hazards of insulin resistance in the recipient mice
.
The above studies suggest that p21high senescent cells in visceral adipose tissue lead to an important mechanism for the development of insulin resistance in obese mice
.
In order to clarify the potential mechanism of p21high senescent cells involved in regulating the occurrence of insulin resistance, the researchers specifically inhibited the NF-κB pathway in p21high senescent cells
.
The results showed that inhibiting NF-κB would not cause changes in the proportion of p21high senescent cells, but the expression of SASP in adipose tissue was significantly reduced, and it could significantly improve the metabolic disorders in obese mice
.
The application of Senolytics (a class of drugs that selectively induce apoptosis of senescent cells) to eliminate accumulated senescent cells or inhibit SASP is currently considered a promising anti-aging strategy [3]
.
In order to explore whether such drugs can target p21high senescent cells to reduce the damage to the body's metabolic function, the researchers selected the widely used senolytic drugs dasatinib (dasatinib, D) and quercetin (quercetin, Q).
), respectively intervene in obese mice and human fat
.
The results showed that the combination of D+Q can significantly reduce the proportion of p21high senescent cells in obese mice and human adipose tissue
.
It is worth mentioning that the researchers transplanted adipose tissue from obese people into immunodeficient mice to establish a xenograft model, and used this model to evaluate the regulation of D+Q on the metabolic function of recipient mice
.
They found that obese human adipose tissue can cause insulin resistance in recipient mice, and after adipose tissue is treated with D+Q administration, insulin resistance in recipient mice is almost eliminated
.
This result clarifies the huge clinical application prospects of targeting p21high senescent cells in improving metabolic disorders
.
The corresponding author of the article, Professor Ming Xu, believes that the results of the human adipose tissue transplantation experiment are impressive, laying the foundation for future D+Q clinical trials
.
Professor Xu emphasized that the clinical test of D+Q treatment effect for patients with type 2 diabetes is currently under planning
.
Before the effectiveness and safety of D+Q are verified by large-scale clinical trials, the drug cannot be used clinically to treat diabetes immediately
.
Figure 1.
Eliminating p21high cells in visceral adipose tissue can effectively improve the metabolic function of adipose tissue.
This article is a re-exploration of the biological functions of p21high senescent cells following the regulation of natural aging
.
In the past, the field of aging research has paid more attention to p16high senescent cells, but this article reveals that p21high senescent cells and p16high senescent cells in the tissues of obese mice are two different cell groups.
There are differences in the regulation of metabolism; compared with p16high senescent cells, p21high senescent cells participate in the regulation of adipose tissue dysfunction more and earlier, resulting in insulin resistance
.
This research also provides a basis for further exploring the characteristics of p21high senescent cells and the possible pathogenic effects of various other aging-related diseases in the natural aging process
.
Dr.
Lichao Wang and Dr.
Binsheng Wang from the Aging Research Center of the University of Connecticut are the first authors of the article, and Professor Ming Xu is the corresponding author of this article
.
Professor Ming Xu’s team mainly uses various mouse models and human tissue samples, and assists in single-cell sequencing, proteomics and other multi-omics technologies to study the role of senescent cells in natural aging and various related diseases, including bodily functions decline, diabetes, Alzheimer's and depression and other neurodegenerative diseases, osteoporosis, bacterial and viral infections, joint disease, and alopecia
.
The laboratory is fully funded and has a good atmosphere.
Now it is open to recruit a number of postdoctoral positions engaged in senescent cell research! Resume delivery (if interested, please send your resume and other materials to): https://jinshuju.
net/f/ZqXwZt or scan the QR code to deliver your resume.
Figure 2.
The main researchers of this research
.
Xu Ming, Wang Binsheng, Wang Lichao (from left to right) Original link: https://doi.
org/10.
1016/j.
cmet.
2021.
11.
002 Platemaker: 11 References 1.
Gasek, NS, Kuchel, GA, Kirkland , JL et al.
Strategies for targeting senescent cells in human disease.
Nat Aging 1, 870–879 (2021).
https://doi.
org/10.
1038/s43587-021-00121-82.
Wang, B.
, Wang, L.
, Gasek, NS et al.
An inducible p21-Cre mouse model to monitor and manipulate p21-highly-expressing senescent cells in vivo.
Nat Aging 1, 962–973 (2021).
https://doi.
org/10.
1038 /s43587-021-00107-63.
Xu, M.
et al.
Senolytics improve physical function and increase lifespan in old age.
Nat.
Med.
24, 1246–1256 (2018).
https://doi.
org/10.
1038/ s41591-018-0092-9 Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights and offenders must be investigated
.
.
The accumulation of senescent cells and the senescence-associated secretory phenotype (SASP) are the hallmarks of body aging, and they are also an important mechanism for the occurrence of senescence and its related chronic diseases
.
In October 2021, Xu Ming's research group at the University of Connecticut reported a new p21-Cre transgenic mouse model for tracking and regulating p21high senescent cells in the body, and found that there are p21high senescent cells in various organs of old mice.
And the specific elimination of the senescent cells can effectively delay the body's aging (see BioArt report: Nature Aging | Xu Ming's team established a p21-Cre mouse model to reveal the role of p21high cells in aging)
.
In addition, the team also detected obvious p21high cell aggregation in obese mice fed high-fat [2]
.
Insulin resistance is one of the main characteristics of type 2 diabetes, and obesity is the key cause of insulin resistance and type 2 diabetes
.
Regarding whether p21high senescent cells are involved in the occurrence of obesity-related insulin resistance, and whether p21high senescent cells can be targeted by drugs to improve insulin resistance and diabetes, these two questions remain to be answered
.
On November 22, 2021, Xu Ming’s team published another long article Targeting p21Cip1-highly-expressing cells in adipose tissue alleviates insulin resistance in obesity in Cell Metabolism, revealing that the accumulation of p21high senescent cells in adipose tissue alleviates insulin resistance in obesity is the cause of insulin resistance.
The drug combination of dasatinib and quercetin can effectively eliminate p21high cells in human adipose tissue and improve the metabolic function of fat transplanted mice
.
This study provides an important basis for using p21high cells as a new therapeutic target for reducing insulin resistance
.
The researchers first used single-cell transcriptome sequencing and found that the adipose tissue of obese mice fed high-fat for two months had a higher level of p21high cells, and they were mainly concentrated in adipose precursor cells, endothelial cells and macrophages; and At the same time, no obvious p16high cells were detected
.
They used the p21-Cre transgenic mouse model constructed earlier and combined with flow cytometry to further confirm the distribution of p21high senescent cells in the adipose tissue of obese mice
.
P21high senescent cells and p16high senescent cells are two common types of senescent cells
.
The researchers then verified the results of single-cell sequencing at the gene and protein levels respectively, that is, the adipose tissue of obese mice fed short-term high-fat diet mainly had accumulation of p21high senescent cells instead of p16high senescent cells
.
Obesity causes adipose tissue expansion and dysfunction, which ultimately leads to insulin resistance and type 2 diabetes
.
To explore whether p21high senescent cells are involved in regulating obesity-related insulin resistance, the researchers crossed p21-Cre mice with floxed DTA (diphtheria toxin A fragment) mice to specifically eliminate p21high senescent cells in the body
.
With the elimination of these cells, the glucose tolerance and insulin sensitivity of obese mice can be significantly improved
.
In addition, the aging-related β-galactosidase activity and telomere DNA damage in the adipose tissue of obese mice after clearing p21high senescent cells were significantly reduced, the cell proliferation ability was effectively restored, and the expression of SASP was also significantly reduced
.
However, the body weight, body fat rate, average daily food intake and activity level of mice did not change significantly, indicating that the elimination of p21high senescent cells mainly works by reducing the degree of tissue aging rather than eating activities in mice
.
In order to confirm the tissue source of p21high senescent cells that cause insulin resistance in obese mice, the researchers first used immunofluorescence and bioluminescence imaging techniques to observe different tissues of obese mice.
They found that p21high senescent cells were mainly distributed in visceral adipose tissue, while the liver , Pancreas, muscle and other tissues are not obvious
.
Next, the researchers transplanted the visceral fat from obese mice to normal mice.
The results showed that the fat transplantation can cause insulin resistance in the recipient mice; and the p21high senescent cells that remove the visceral fat from the donor body can significantly improve the fat transplantation.
The hazards of insulin resistance in the recipient mice
.
The above studies suggest that p21high senescent cells in visceral adipose tissue lead to an important mechanism for the development of insulin resistance in obese mice
.
In order to clarify the potential mechanism of p21high senescent cells involved in regulating the occurrence of insulin resistance, the researchers specifically inhibited the NF-κB pathway in p21high senescent cells
.
The results showed that inhibiting NF-κB would not cause changes in the proportion of p21high senescent cells, but the expression of SASP in adipose tissue was significantly reduced, and it could significantly improve the metabolic disorders in obese mice
.
The application of Senolytics (a class of drugs that selectively induce apoptosis of senescent cells) to eliminate accumulated senescent cells or inhibit SASP is currently considered a promising anti-aging strategy [3]
.
In order to explore whether such drugs can target p21high senescent cells to reduce the damage to the body's metabolic function, the researchers selected the widely used senolytic drugs dasatinib (dasatinib, D) and quercetin (quercetin, Q).
), respectively intervene in obese mice and human fat
.
The results showed that the combination of D+Q can significantly reduce the proportion of p21high senescent cells in obese mice and human adipose tissue
.
It is worth mentioning that the researchers transplanted adipose tissue from obese people into immunodeficient mice to establish a xenograft model, and used this model to evaluate the regulation of D+Q on the metabolic function of recipient mice
.
They found that obese human adipose tissue can cause insulin resistance in recipient mice, and after adipose tissue is treated with D+Q administration, insulin resistance in recipient mice is almost eliminated
.
This result clarifies the huge clinical application prospects of targeting p21high senescent cells in improving metabolic disorders
.
The corresponding author of the article, Professor Ming Xu, believes that the results of the human adipose tissue transplantation experiment are impressive, laying the foundation for future D+Q clinical trials
.
Professor Xu emphasized that the clinical test of D+Q treatment effect for patients with type 2 diabetes is currently under planning
.
Before the effectiveness and safety of D+Q are verified by large-scale clinical trials, the drug cannot be used clinically to treat diabetes immediately
.
Figure 1.
Eliminating p21high cells in visceral adipose tissue can effectively improve the metabolic function of adipose tissue.
This article is a re-exploration of the biological functions of p21high senescent cells following the regulation of natural aging
.
In the past, the field of aging research has paid more attention to p16high senescent cells, but this article reveals that p21high senescent cells and p16high senescent cells in the tissues of obese mice are two different cell groups.
There are differences in the regulation of metabolism; compared with p16high senescent cells, p21high senescent cells participate in the regulation of adipose tissue dysfunction more and earlier, resulting in insulin resistance
.
This research also provides a basis for further exploring the characteristics of p21high senescent cells and the possible pathogenic effects of various other aging-related diseases in the natural aging process
.
Dr.
Lichao Wang and Dr.
Binsheng Wang from the Aging Research Center of the University of Connecticut are the first authors of the article, and Professor Ming Xu is the corresponding author of this article
.
Professor Ming Xu’s team mainly uses various mouse models and human tissue samples, and assists in single-cell sequencing, proteomics and other multi-omics technologies to study the role of senescent cells in natural aging and various related diseases, including bodily functions decline, diabetes, Alzheimer's and depression and other neurodegenerative diseases, osteoporosis, bacterial and viral infections, joint disease, and alopecia
.
The laboratory is fully funded and has a good atmosphere.
Now it is open to recruit a number of postdoctoral positions engaged in senescent cell research! Resume delivery (if interested, please send your resume and other materials to): https://jinshuju.
net/f/ZqXwZt or scan the QR code to deliver your resume.
Figure 2.
The main researchers of this research
.
Xu Ming, Wang Binsheng, Wang Lichao (from left to right) Original link: https://doi.
org/10.
1016/j.
cmet.
2021.
11.
002 Platemaker: 11 References 1.
Gasek, NS, Kuchel, GA, Kirkland , JL et al.
Strategies for targeting senescent cells in human disease.
Nat Aging 1, 870–879 (2021).
https://doi.
org/10.
1038/s43587-021-00121-82.
Wang, B.
, Wang, L.
, Gasek, NS et al.
An inducible p21-Cre mouse model to monitor and manipulate p21-highly-expressing senescent cells in vivo.
Nat Aging 1, 962–973 (2021).
https://doi.
org/10.
1038 /s43587-021-00107-63.
Xu, M.
et al.
Senolytics improve physical function and increase lifespan in old age.
Nat.
Med.
24, 1246–1256 (2018).
https://doi.
org/10.
1038/ s41591-018-0092-9 Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights and offenders must be investigated
.
