Weizmann Institute of Science scientists reveal that aging cells escape our immune system similar to cancer cells, and point the way for innovative treatment of aging diseases and chronic inflammations
In order for the sink to overflow, two conditions must be met - running water and a blocked drain opening. When we age, our body is flooded with "senescent" cells - cells that stop dividing, and instead of dying and clearing their way, remain active and accumulate. Studies from recent years have shown that eliminating them may delay the onset of old age diseases, reduce inflammation and prolong life. However, despite the great promise, there is currently no drug that damages these cells in a targeted and effective manner. Now, Weizmann Institute of Science scientists reveal the other side of the equation: how the aging cells "clog" the immune system's drain opening and prevent it from doing its job and getting rid of them. onA recently published study in the scientific journal Nature Cell Biology, The researchers showed that this "blockage" can be released through immunotherapy - that new generation of treatments that are revolutionizing the field of cancer medicine. These findings in mice may pave the way for innovative treatments for old age and other chronic diseases.
the laboratory of Prof. Valery Kryzhnovsky In the department of molecular biology of the cell at the institute, the biological processes that characterize aging and in particular the involvement of aging cells in chronic inflammation and senile diseases have been researched for years. A mathematical model developed in 2019 by Prof. Uri Alon from the institute in collaboration with Prof. Krizhnovsky predicted that while at a young age senescent cells are removed from the body within a few days and therefore do not accumulate, in old age they manage to delay their own removal. Now, in a study led by Dr. Julia Majowska and Dr. Amit Agarwal, the researchers reveal the mechanism that makes this possible - evading the immune system in a mechanism similar to that which occurs in cancer. The researchers discovered that aging lung cells in mice express high levels of proteins that suppress the immune system, in particular the protein PD-L1. This protein is a household name in the field of cancer medicine and a prominent target for drug development, as it is known that cancer cells use it to damage the immune system's ability to recognize and destroy them.
"The treatment did not stop the biological clock, but it managed to eliminate aging cells in the mice and even reduce the secretion of pro-inflammatory proteins"
But how is the overexpression of a protein that suppresses the immune system in these cells created in the first place? Well, the cell aging process is likened to pressing the gas and the brakes at the same time: on the one hand, pressing the gas pedal causes the cell to continue to be very active, and on the other hand, pressing the brakes causes its normal life cycle to stop and its division to stop; It is precisely for this reason that these cells are sometimes called "zombies". A central component of the brake pedal is the protein p16 which inhibits DNA replication in the cell. The scientists identified in the study that there is a correlation between the increase in p16 during cell aging and the increase in PD-L1 levels. They even cracked the molecular mechanism behind this increase: p16 inhibits a natural process in the cell that marks PD-L1 proteins as destined for degradation.
Not for adults only
But senescent cells are important not only in old age, and Prof. Krzyznovsky's group has already shown in the past that their accumulation plays a role in chronic lung diseases, among other things. In the current study, the researchers showed that the increase in the PD-L1 protein occurs not only in old age, but also in a mouse model of chronic obstructive pulmonary disease (COPD) - a disease that characterizes most smokers. The scientists were not satisfied with a mouse model and revealed that even in humans with COPD there are senescent cells that express high levels of p16 and PD-L1.
When it became clear that aging cells, like cancer cells, express high levels of PD-L1 which helps them escape the immune system, the researchers hypothesized that it would be possible to use this fact to damage the aging cells in a relatively targeted manner, for example using an antibody approved for use in various types of cancer that can detect PD -L1 on the envelope of cells and activate cells of the immune system against it. The researchers tested the action of the antibody in aging mice as well as in mice with short-term and chronic inflammatory lesions in the lung. In accordance with the hypotheses, the treatment with the antibody stimulated the T cells - the fighters of the immune system - and other immune cells into action and led to a reduction in the aging cell population.
"The treatment we tested did not stop the biological clock, but it was able to eliminate aging cells in mice and even reduce the secretion of small proteins that promote inflammation in old age and chronic diseases," says Prof. Krzyznovsky. "PD-L1 is expressed at high levels in aging cells but not only in them, therefore we believe that the key to creating a targeted and effective treatment will be to engineer antibodies that recognize two proteins at the same time - PD-L1 and another marker of aging. This discovery gives hope that immunotherapy can be used in the future as a treatment not only for cancer but also in chronic inflammations and diseases of old age."
Dr. Avi Mayo, Lior Roitman, Ilanit Sofer, Dr. Avi Maimon and Prof. Uri Alon from the department of molecular cell biology at the institute also participated in the study; Rishita Chatterjee and Dr. Jarmila Karlova from the Department of Immunology and Biological Regeneration at the Institute; Dr. Tomer Landsberger, Yonatan Katzenlenbogen and Prof. Ido Amit from the Department of Systemic Immunology at the Institute; Dr. Tomer Meir Selma and Dr. Efrat Hagai from the Department of Research Infrastructures Life Sciences at the Institute; Juan-Felipe Perez-Correa and Prof. Wolfgang Wagner from the Technical University of Rhine-Westphalia in Germany (RWTH Aachen).
