Afraid of aging? Learn about this "young factor"

Afraid of aging? Learn about this "young factor"

April 30, 2019 Source: Voice of the Chinese Academy of Sciences

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There are reopening days for flowers, and there are no more people.

As life goes by, life and death are the problems that everyone will face.

In 2016, the international academic journal Science published “Cleaning the aging cells to keep the body young” as one of the top ten scientific breakthroughs of the year, indicating the important role of cell aging in the body's aging.

As the saying goes, "There is old, then there is illness."

So how do we delay aging?

How to achieve "old but not bad", "old and less sick"?

There are a class of adult stem cells in various human tissues such as bone marrow, fat, gums and joints, which are called "mesenchymal stem cells". Mesenchymal stem cells play an important role in the maintenance of tissue function and homeostasis, while the senescence and depletion of mesenchymal stem cells lead to the development of various senile diseases.

As a common aging-related disease, osteoarthritis has an increasing incidence with age. More than half of the elderly over the age of 60 suffer from this disease. With the increase of age, various cell types including chondrocytes, synovial cells and mesenchymal stem cells undergo aging and functional deterioration. Among them, the aging of mesenchymal stem cells is considered to be one of the main causes of the onset of osteoarthritis. Therefore, if the key targets of mesenchymal stem cell senescence can be found and intervened, and the aging mesenchymal stem cells can be rejuvenated, it may be effective in treating osteoarthritis. Accordingly, researchers have been working hard to explore factors that can restore human mesenchymal stem cells to a "young state."

Another feature of YAP - "de-aging"

The researchers screened and identified multiple single-protein factors that maintain the young state of human mesenchymal stem cells. YAP is one of them.

YAP is a downstream effector of the Hippo pathway. As a transcriptional coactivator, YAP functions after a series of kinase phosphorylation reactions. Previous studies have shown that YAP is involved in the regulation of important cell life activities such as cell adhesion, cell polarity, and cytoskeletal assembly.

To further investigate the role of YAP in the senescence of human mesenchymal stem cells, the researchers used CRISPR/Cas9-mediated gene editing techniques to obtain YAP-specific knockout human embryonic stem cells. Human embryonic stem cells are then induced to differentiate into mesenchymal stem cells by directed differentiation techniques. YAP-deficient human mesenchymal stem cells have a severe accelerated aging phenotype compared to normal human mesenchymal stem cells. Moreover, overexpression of YAP in YAP-deficient human mesenchymal stem cells can effectively reverse the accelerated aging phenotype of cells. This suggests that YAP plays a key role in maintaining young adult stem cells and may have a "de-aging" effect.

YAP "de-aging" mechanism

YAP plays the role of “young factor” in human mesenchymal stem cells, so what is its mechanism of action? Because YAP has the function of a transcriptional coactivator, the researchers performed transcriptome sequencing analysis of normal and YAP-deficient human mesenchymal stem cells and transcription factor binding elements, and concluded that FOXD1 may be a novel target gene for YAP.

To test this inference, the researchers used chromatin immunoprecipitation and fluorescence reporter systems to demonstrate that YAP binds to another transcription factor TEAD, binds to a specific region of the promoter of the FOXD1 gene, and regulates transcription of the FOXD1 gene. Achieve regulation of cellular aging processes.

In addition, the researchers also found that YAP and FOXD1 are a community of fate, consistently down-regulated in a variety of human mesenchymal stem cell aging models. Moreover, overexpression of "young factors" YAP and FOXD1 in these senescent cells delays or reverses cellular senescence.

"Young factor" helps treat aging-related diseases

At the cellular level, the "young pathway" of YAP-FOXD1 demonstrates the function of "de-aging". So, at the individual level, do these “young factors” also have this effect?

The researchers established an in vivo model of osteoarthritis by cutting off the anterior cruciate ligament of the mouse. Subsequently, a lentiviral vector was used as a gene introduction vector, and a lentivirus encoding a YAP or FOXD1 protein was injected into a joint cavity of a mouse having osteoarthritis. The study found that several weeks of YAP or FOXD1 gene therapy can significantly reduce the proportion of aging cells in articular cartilage, effectively inhibit joint cartilage degradation and joint cavity inflammation, and improve the pathological phenotype of osteoarthritis in many ways.

This study conceptually and experimentally demonstrated the effectiveness of two "young factors", YAP and FOXD1, as targets for osteoarthritis gene therapy.

In the future, researchers will continue to discover new young factors, provide more clear targets for gene therapy, and ultimately provide more solutions for aging-related diseases.

However, it should be noted that this achievement is still in the research stage and has not been translated into related products or clinical applications. If there are similar false medical advertisements, please do not believe it.

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