A recent investigation has identified a connection between inflammation from senescent cells and a protein essential for the organization of DNA.
Researchers at Sanford Burnham Prebys and the La Jolla Institute for Immunology have uncovered new insights about cellular senescence, a state akin to sleep that predominantly impacts older cells. While this dormant condition can be beneficial in specific contexts, it also has the potential to cause harm.
“Senescence isn’t entirely negative,” noted Peter D. Adams, PhD, who heads the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys and is the lead author of the new research. “It acts as a safeguard against cancer by inhibiting the growth of potentially malignant cells.”
“It also plays a role in managing the wound healing process,” added Nirmalya Dasgupta, PhD, an instructor at the La Jolla Institute for Immunology and the lead author of the study. “Via its inflammatory properties, it regulates tissue repair and healing.”
However, with aging and the immune system struggling to eliminate senescent cells, these dormant cells can build up to unhealthy levels, hindering the regeneration of tissues.
“Apart from ceasing to grow and replicate, a key feature of senescent cells is their inflammatory program, which leads them to release inflammatory substances,” stated Adams.
An excess of these substances can lead to chronic inflammation in the body. This widespread inflammation, referred to as “inflammaging,” is associated with numerous age-related conditions, including rheumatoid arthritis, liver ailments, atherosclerosis, muscle wasting (sarcopenia), and cancer.
On August 22, 2024, Adams, Dasgupta, and their team published findings in Molecular Cell, showcasing a novel link between inflammation from senescent cells and a protein that plays a role in tightly packaging six feet of DNA within the cell’s nucleus.
The researchers elaborated on how this protein affects the rise in inflammation when cells enter their dormant state. By exploring this mechanism, the authors may have identified a new avenue for developing drugs aimed at fostering healthy aging by minimizing or preventing chronic inflammation caused by excessive senescent cells as we age.
The research team began by altering cells to disable the gene coding for the HIRA protein, a histone chaperone crucial for forming spools from histones that hold DNA securely. They also silenced the gene responsible for the promyelocytic leukemia (PML) protein, which organizes many proteins involved in various functions, including DNA replication during cell growth and RNA transcription for protein synthesis. The researchers then induced senescence in these cells and compared them with normal senescent cells.
The modified cells, lacking HIRA and PML, still retained their dormant state and inability to grow. However, these proteins were essential for triggering the release of inflammatory substances that contribute to inflammaging, known as the senescence-associated secretory phenotype (SASP).
“Some believe that eliminating senescent cells could enhance healthy aging,” said Dasgupta. “Alternatively, one could argue that senescence has evolutionary significance, and removing it might prove detrimental. From this perspective, alleviating the inflammation from SASP could be more beneficial and less risky, making it essential to understand its triggers.”
Subsequent experiments showed that HIRA must relocate to PML nuclear bodies for senescent cells to trigger their inflammatory response. The researchers also discovered HIRA’s vital role in activating the signaling pathway that signals senescent cells to release inflammatory substances. Additionally, they identified a new interaction between HIRA and a protein called p62, which helps limit the release of inflammatory molecules.
“These findings reveal a novel pathway and new components in the initiation of the inflammatory program in senescent cells,” remarked Adams. “This insight opens more possibilities to explore new drugs aimed at inhibiting this process.”
According to Adams, the research team will collaborate with the Sanford Burnham Prebys’ Conrad Prebys Center for Chemical Genomics to identify small molecules that target the newly established pathway. The Prebys Center specializes in drug discovery and chemical biology.
In addition to developing new medications, there may be opportunities to repurpose existing drugs. Dasgupta mentioned that at least four drugs currently undergoing clinical trials for cancer might be effective in preventing HIRA from moving to PML nuclear bodies. This movement is necessary for senescent cells to release inflammatory molecules, making drugs capable of obstructing HIRA’s relocation to PML nuclear bodies promising candidates for future research aimed at promoting healthy aging.
“Our findings will also accelerate the initiatives of the SenNet Consortium as we work towards creating a detailed map of the characteristics and locations of senescent cells,” notes Adams.
Adams co-leads the San Diego Tissue Mapping Center as part of the Cellular Senescence Network (SenNet) Consortium, a vast network of U.S. laboratories and research institutions funded by the National Institutes of Health’s Common Fund. The NIH is set to grant over $190 million in SenNet funding by 2026.
“Together with our partners in the consortium, we aim to understand what senescent cells look like on a molecular level,” stated Adams. “Our goal is to uncover the gene expression patterns and signaling pathways activated in these cells across different cell types and tissues.”
“With Nirmalya and the team, we have revealed another piece of the larger puzzle we are assembling. Creating a comprehensive map of senescence will enable more effective targeting of senescent cells with treatments for better aging.”
Additional contributors to the study include Xue Lei, Christina Huan Shi, Rouven Arnold, Marcos G. Teneche, Karl N. Miller, Adarsh Rajesh, Andrew Davis, Valesca Anschau, Alexandre R. Campos, Rebecca Gilson, Aaron Havas, Shanshan Yin, Zong Ming Chua, Tianhui Liu, Jessica Proulx, Michael Alcaraz, Mohammed Iqbal Rather, Josue Baeza, David C. Schultz, Kevin Y. Yip, and Shelley L. Berger.
The study received support from the National Institutes of Health’s National Institute on Aging, the Glenn Foundation for Medical Research, and the American Federation for Aging Research.
