The secret of sleeping cells controlling inflammatory secretions

Scientists at Sanford Burnham Prebys and the La Jolla Institute for Immunology have revealed a new secret about senescence, a sleep-like cellular state that is more likely to affect older cells. This sleepy state is known to be beneficial to health in certain conditions, but can also cause collateral damage.

“Senescence is not entirely bad,” said Peter D. Adams, Ph.D., director of the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys and senior author of the new study. “It’s a tumor suppression mechanism that prevents cancer by blocking the proliferation of potentially cancerous cells.”

“It also helps orchestrate the wound healing response,” added Nirmalya Dasgupta, Ph.D., professor at the La Jolla Institute for Immunology, a former postdoctoral associate in Adams’ lab, and first author of the study. “Through its inflammatory function, it can control tissue repair and wound healing.”

However, senescence can be a double-edged sword, with age and the immune system becoming less effective at clearing out senescent cells. When these dormant cells accumulate to unhealthy levels, they can prevent aging tissues from regenerating properly.

“In addition to no longer growing and proliferating, the other characteristic of senescent cells is that they have this inflammatory program that causes them to secrete inflammatory molecules,” Adams said.

Excessive secretion of these molecules can contribute to chronic inflammation in the body. This widespread inflammation, called “inflammaging,” has been linked to many age-related diseases, such as rheumatoid arthritis, liver disease, atherosclerosis, muscle wasting (sarcopenia), and cancer.

Adams, Dasgupta and their collaborators published results in Molecular celldescribing a new link between inflammation caused by senescent cells and a protein involved in the process of winding six feet of DNA tightly enough to fit into the nuclear center of cells.

Scientists have defined how this protein influences the increase in inflammation when our cells enter a state of sleep. By detailing this process, the authors may have discovered a new opportunity to find drugs that can promote healthy aging by preventing or reducing chronic inflammation due to the excessive accumulation of senescent cells as we age.

The research team began by modifying the cells to disable the gene that codes for the protein HIRA, one of the histone chaperones responsible for building the histone coils used to hold DNA together like a thread.

They also silenced the gene for the promyelocytic leukemia protein (PML), which, when contained in tiny, dense spheres called nuclear bodies, serves as an anchor and organizer for many proteins involved in a wide variety of functions, including replicating complete copies of DNA during cell growth and transcribing DNA into RNA during the construction of new proteins. The scientists then forced the cells to become senescent and compared the engineered cells to normal senescent cells.

The absence of HIRA and PML in the engineered cells did not reverse the dormant cells’ lack of growth and proliferation. Both proteins were found to be necessary for cells to begin emitting the inflammatory molecules that can lead to inflammation, known as the senescence-associated secretory phenotype (SASP).

“One school of thought is that we should eliminate senescent cells to promote healthier aging,” Dasgupta said. “Another view is that senescence has played a role throughout evolution, so eliminating it could be detrimental. According to this view, reducing inflammation due to SASP might be more helpful and less risky, so it’s critical to learn more about its causes.”

The research team followed up with additional experiments that demonstrated that HIRA must migrate to PML nuclear bodies for senescent cells to enter their inflammatory state. The scientists also discovered that HIRA was essential for activating the cellular signaling pathway that is considered the primary route by which senescent cells begin to expel inflammatory molecules.

In addition, the team discovered a novel behavior of HIRA in the gelatinous cytoplasm that occupies the space in the cell between the membrane and the nucleus. HIRA physically interacts with a protein called p62 that reduces the secretion of inflammatory molecules.

“With these results, we have defined a new pathway and new players in the process that triggers the inflammatory program of senescent cells,” Adams said. “This knowledge offers new possibilities for trying to find new drugs to inhibit this process.”

Adams said the team will continue this research by collaborating with the team at the Conrad Prebys Center for Chemical Genomics (Prebys Center) at Sanford Burnham Prebys to identify small molecules that target the newly defined pathway. The Prebys Center is a comprehensive drug discovery and chemical biology center.

In addition to discovering new drugs, it may be possible to repurpose existing drugs. Dasgupta said that at least four drugs currently in clinical trials for cancer may be effective in blocking HIRA from being transported to PML nuclear bodies. This movement by HIRA has been shown to be necessary for senescent cells to secrete inflammatory molecules, pointing to drugs that can stop HIRA from localizing to PML nuclear bodies as candidates for future research into treatments for healthy aging.

“Our results will also help accelerate the work of the SenNet Consortium as we continue to develop a detailed map of where these senescent cells are located and what they look like,” Adams notes.

Adams co-directs the San Diego Tissue Mapping Center within the Cellular Senescence Network (SenNet) Consortium, a large network of U.S. laboratories and research institutes.

“With our consortium partners, we want to know what senescent cells look like at the molecular level,” Adams said. “We are looking for the gene expression programs and signaling pathways that are activated in these cells, across different cell types and tissues. With Nirmalya and her team, we have now discovered another piece of the larger puzzle that we are piecing together. Developing a comprehensive map of senescence will allow us to better target senescent cells with treatments to promote healthy aging.”