Delaying aging process by selective removal of senescent cells

A recent study, led by an international team of researchers confirms that targeted removal of senescent cells (SnCs), accumulated in many vertebrate tissues as we age, contribute significantly in delaying the onset of age-related pathologies.

Credit: Baker et al., Nature 

This breakthrough research has been led by Dr. Chaekyu Kim and Dr. Ok Hee Jeon. In the study, the research team presented a novel pharmacologic candidate that alleviates age-related degenerative joint conditions, such as osteoarthritis (OA) by selectively destroying SnCs. Their findings, published in Nature Medicine, suggest that the selective removal of old cells from joints could reduce the development of post-traumatic OA and allow new cartilage to grow and repair joints.

To test the idea that SnCs might play a causative role in OA, the research team took both younger and older mice and cut their anterior cruciate ligaments (ACL) to minic injury. They, then, administered injections of an experimental drug, named UBX0101 to selectively remove SnCs after anterior cruciate ligament transection (ACLT) surgery.

Preclinical studies in mice and human cells suggested that the removal of SnCs significantly reduced the development of post-traumatic OA and related pain and created a prochondrogenic environment for new cartilage to grow and repair joints. Indeed, the research team reported that aged mice did not exhibit signs of cartilage regeneration after treatment with UBX0101 injections,

According to the research team, the relevance of their findings to human disease was validated using chondrocytes isolated from arthritic patients. The research team notes that their findings provide new insights into therapies targeting SnCs for the treatment of trauma and age-related degenerative joint disease.

Citation: Jeon, Ok Hee, Chaekyu Kim, Remi-Martin Laberge, Marco Demaria, Sona Rathod, Alain P. Vasserot, Jae Wook Chung, Do Hun Kim, Yan Poon, Nathaniel David, Darren J. Baker, Jan M Van Deursen, Judith Campisi, and Jennifer H. Elisseeff. “Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment.” Nature Medicine 23, no. 6 (2017): 775-81.
Adapted from press release by the Uslan National Institute of Science and Technology.

Research identifies protein behind side effects of cellular senescence

Cellular senescence is a state in which normal healthy cells do not have the ability to divide. Senescence can occur when cancer-causing genes are activated in normal cells or when chemotherapy is used on cancer cells. Thus, senescence induces a mechanism that halts the growth of rapidly dividing cells. Once thought to only be beneficial to halt cancer progression, work from the The Wistar Institute has shown that during senescence there is an increase in secreted factors called cytokines and chemokines (small proteins important in immune responses) that may have detrimental, pro-tumorigenic side effects.

Researchers at The Wistar Institute have identified a protein that plays a critical role in the expression of cytokines and chemokines, and that decreasing this protein suppresses the expression of these secreted factors. This suggests that there may be ways of promoting the positive effects of senescence while suppressing its negative effects. The findings were published online by the Journal of Cell Biology.

Rugang Zhang, Ph.D., professor and co-program leader of the Gene Expression and Regulation program at Wistar, and colleagues focused on chromatin, a cellular structure responsible for holding the DNA in our cells together. During senescence, some of the chromatin is reorganized into senescence-associated heterochromatin foci (SAHF). When this happens, genes that are responsible for promoting proliferation are silenced. However, the expression of cytokine and chemokine genes  known collectively as the senescence-associated secretory phenotype (SASP) is increased.

“When senescence happens, you have two closely linked phenomena occurring, yet one of these helps to halt tumor progression while the other causes an increase in potentially harmful inflammatory cytokines and chemokines,” said Zhang, who is lead author of the study. “We pinpointed the architecture of chromatin and the proteins that influence chromatin organization as the proper place to start to try and solve this paradox.”

The scientists looked at a set of proteins known as high mobility group proteins, which are responsible for altering chromatin architecture in order to regulate gene transcription. One such protein called high mobility group box 2 (HMGB2) binds to DNA to increase chromatin’s accessibility to transcription factors. They showed that high mobility group box 2 (HMGB2) promotes senescence-associated secretory phenotype (SASP) gene expression by preventing the spreading of heterochromatin and therefore preventing senescence-associated heterochromatin foci (SAHF) from silencing senescence-associated secretory phenotype (SASP) genes. When the researchers silenced high mobility group box 2 (HMGB2), senescence-associated secretory phenotype (SASP) genes were successfully silenced by SAHF, suggesting that the detrimental effects of senescence might be negated by inhibiting high mobility group box 2 (HMGB2).

“Understanding senescence is critical for understanding how tumor growth can be successfully suppressed,” said Katherine Aird, Ph.D., a staff scientist in the Zhang lab and first author of the study. “With the information from this study, we may be able to increase the effectiveness of chemotherapeutic agents that are able to induce senescence by silencing high mobility group box 2 (HMGB2) and decreasing the expression of unwanted secreted factors.”

Citation: HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci. Katherine M. Aird, Osamu Iwasaki, Andrew V. Kossenkov, Hideki Tanizawa, Nail Fatkhutdinov, Benjamin G. Bitler, Linh Le, Gretchen Alicea, Ting-Lin Yang, F. Brad Johnson, Ken-ichi Noma, Rugang Zhang. Journal of Cell Biology Oct 2016, jcb.201608026;
Research funding: National Institutes of Health, NIH/National Cancer Institute, Ovarian Cancer Research Fund Alliance, The Jayne Koskinas & Ted Giovanis Breast Cancer Research Consortium at Wistar, Russian Government Program.
Adapted from press release by The Wistar Institute

Genes that control cellular senescence identified

Adapted from press release by Kobe University

A research group including Professor Kamada Shinji, Research Fellow Nagano Taiki (both from the Kobe University Biosignal Research Center), and Unit Chief Enari Masato (National Cancer Research Institute) has succeeded in identifying genes that control cellular senescence – permanently arrested cell growth. The process involved treating liver cancer cells using anticancer drugs of various concentrations, inducing apoptotic cell death and cellular senescence, and comparing gene expression levels. By developing drugs that suppress the activity of these genes, this discovery has potential applications for creating new highly-effective anticancer drugs, or use in anti-aging drugs. The results of this research were published on August 22 in the online version of Scientific Reports.

Living organisms experience various stresses during their lifespans. These stresses include radiation, ultraviolet rays, and chemical substances that directly damage DNA and cause cancer. Organisms are able to speedily repair DNA when it is damaged, but when the damage is severe, they manifest two different cell responses: apoptosis – a type of controlled cell death – and cellular senescence, which permanently suspends cell growth. Both these responses prevent the cell which suffered DNA damage from proliferating and becoming cancerous.

Cancer treatment based on radiation and anticancer drugs aims to destroy cancer tissue by triggering apoptosis in cancerous cells. However, it is thought that this treatment is itself a stress factor that induces cell mutation, causing changes in the cancerous cells. These cells produce clones that have acquired resistance against the treatment, leading to a relapse. One of the changes in cancerous cells caused by this treatment is the appearance of senescent cells. It has been suggested that by secreting various proteins, senescent cells may accelerate the proliferation and malignant transformation of surrounding cancer cells.

The research group had previously discovered that cell senescence was effectively induced by using low concentrations of anticancer drugs on cancerous cells. In anticancer treatment, drugs are carried to the cancerous tissue via the bloodstream. The researchers predicted that differences in concentrations of the anticancer drugs would arise based on the distance of the cells from the blood vessels, and so even in the normal cancer treatment process senescent cells would emerge. Therefore, if we simultaneously administer a medicine that inhibits cell senescence during standard cancer treatment, there is the potential for a dramatic increase in treatment effectiveness.

Previously the research group found that if cancerous cells are treated with a low concentration (10 μM) of the anticancer drug etoposide this induces cell senescence, and if they are treated with a high concentration of the drug (100 μM) this induces apoptosis. For this research, they treated cancerous cells under three different conditions: A) with no etoposide; B) with a low dose of etoposide (10 μM); and C) with a high dose of etoposide (100 μM). They then used DNA microarrays¹ to identify the genes in which a rise in transcription levels could be observed.

They predicted that genes which showed increased expression in response to treatment B were mainly related to cell senescence, genes expressed in response to C were mainly those involved in apoptosis, and among the genes which specifically showed increased expression in B compared to C would be genes that play an important role in implementing cell senescence.

There were 126 genes where three times as much expression was recorded under treatment B compared to A, and 25 genes that showed twice as much expression in B compared to C. These 25 genes are expected to express specifically in senescent cells since the other factors caused by DNA damage are removed, and researchers confirmed that the genes involved in causing cell senescence were among them.

If we can develop a drug that targets and regulates the activity of the genes that control senescence identified in this research, by administering it together with conventional anticancer treatment we can limit the emergence of senescent cells and potentially increase the effectiveness of cancer treatment. Additionally, it has been reported that one of the causes of individual aging is the accumulation of senescent cells. This means that drugs which control cell senescence could have potentially large benefits for the development of anti-aging medication products related to health and beauty.