Harvard Medical School: Dasatinib and Quercetin Could Be Used to Rejuvenate Older Organs for Transplantation

Organ transplantation is a crucial aspect of modern medicine and responsible for saving millions of lives. It depends on organ donors, whether alive or deceased. However, there is a strict criterion to follow when selecting organ donors. In simple terms, the donor must be healthy and young. This narrow organ pool combined with an increased need for organs has resulted in more recipients than donors, with a lot of recipients all waiting on the transplant list for an organ.  Dasatinib

 

Is there a way to bridge the gap?

This massive gap between the two groups has caused researchers to look into an alternative to provide organs for these patients. Iske and his colleagues from Brigham and Women’s Hospital, Harvard Medical School, Boston recently published a study they performed in the Nature Communications Journal. The aim of their study was to investigate a way to use organs from older deceased individuals.

Read Also: Transplantation: Damaged Lungs Restored With Live Pig’s Blood

Why are older donors ostracised?

Organs from older donors are usually not considered, because of the higher risk of adverse effects associated with them. Studies have found that older organs usually have a certain type of cells called senescent cells. These cells are no longer going through the cell cycle and evade the elimination process which is usually applied to older cells.

Senescent cells are associated with a higher rate of transplant rejection. Transplant rejection can result in decreased quality of life and sometimes, even death. This would explain the medical community’s hesitation in using older organs which have been shown to contain accumulations of senescent cells.

Read Also: Senolytic Agents: The Potential Forerunners in the Fight Against Aging

Researchers have realized the mechanism of this rejection. Senescent cells release free mitochondrial DNA, which in turn activates dendritic cells. These cells lead to augmented IL6 response along with costimulatory molecules CD40/CD80. The increased IL6 levels are related to inflammation and a massive whirlwind increase in cytokines. This increase in cytokines and increased inflammatory response is related to organ rejection.

What is the solution to senescent cells?

Iske and colleagues from Harvard found that a specific class of drugs called senolytics may push these senescent cells back into the cell cycle. This is of importance because the cell cycle usually removes old, aged cells. The study performed aimed to apply this theoretical concept to animal models. The researchers wanted to determine if this concept can be practically applied.

Method of the study

The team of researchers with Iske used two senolytic drugs, Dasatinib and Quercetin. These drugs were given to mice for 3 days, at a dosage of 5mg/kg and 50mg/kg respectively. On the fourth day, researchers prepped the mice for cardiac transplants. They then assessed the mitochondrial DNA levels and inflammation levels usually associated with senescent cells.

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Results of Brigham and Women’s Hospital’s Study

Both the experimental and clinical studies performed by Iske and colleagues showed higher levels of mitochondrial DNA in organs from older donors. Clinically, the peripheral blood sample from the older, deceased donors showed a high amount of senescent cells. Experimentally, the results were similar.

The use of senolytics depended on blocking pro-survival pathways for senescent cells and it showed great results, according to the researchers. These drugs blocked those pathways by blocking IL6 and inhibiting the activation of dendritic cells, all the mechanisms associated with organ failure.

Senolytics slowed down the aging and deterioration of organ function normally associated with senescence. This normal functioning of organs, plus the decrease in free mitochondrial DNA all together showed positive results in the animal models used by the researchers.

It is important to note that the study performed by Iske only showed results in animal models, and they recommend a detailed clinical trial to be performed to ensure the results of their experimental study.

However, this is a giant step in the right direction. The study by these researchers may have just given the medical community a solution to their biggest problem.

Read Also: Corneal Perforations Can Now Be Fixed Permanently Without the Need for a Transplant According to University of Montreal Researchers

References

Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation

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