Pitt/UPMC Take a Leading Role in NIH’s Ambitious Cellular Senescence Network (SenNet) Program to Identify, Examine, Characterize, Map Senescent Cell Populations Throughout the Body and Across the Lifespan

The Cellular Senescence Network (SenNet) program launched in 2021 by the National Institutes of Health's (NIH) Common Fund to comprehensively examine senescent cells, which due to varying factors, cease to replicate but continue to function and accumulate in tissues and organs.

The SenNet program seeks to answer fundamental questions about how and why cells take on a senescent state, the roles and functionality they exhibit, and their distribution throughout the human body, which remains largely unknown due to their scarcity and heterogeneity, but are beginning to reveal their nature, locations, and functionality by way of advances in computational analytics, single-cell analysis techniques, spatial mapping technologies, and other emerging research advances.

The primary objectives of SenNet include the identification and characterization of these cells across different states of health, in varying tissues and organs, and throughout the lifespan – from the neonate to the very old. The program will generate public atlases detailing the diversity of senescent cells, the molecules they produce, and how these cellular products may drive both beneficial or harmful processes.

Ultimately, the project aims to create a common language and classification for these cells, thereby facilitating collaborations among researchers. The data and resources generated will accelerate the development of therapies targeting senescent cell populations and characteristics that factor into disease processes.

The University of Pittsburgh and UPMC researchers have been tapped to lead two important components of the SenNet program (details below).

What is Cellular Senescence and its Functional Duality?

Cellular senescence refers to a state where cells lose their ability to divide and function properly. Initially identified as a biological process preventing unlimited cell proliferation and thus acting as a barrier to developing cancers, senescence has since been recognized as a complex phenomenon with implications far beyond tumor suppression.

Senescent cells accumulate in tissues over time due to aging, environmental stress, and certain disease processes. Although these cells cease to divide and replicate themselves, they remain metabolically active and often develop a unique phenotype characterized by changes in cell morphology, function, and secretory activity. This senescence-associated secretory phenotype (SASP) involves the production and release of various bioactive molecules, including pro-inflammatory cytokines, chemokines, and growth factors, which can significantly impact the surrounding tissue microenvironment and the organism's overall health.

While senescence has protective roles like suppressing tumorigenesis and aiding tissue repair, chronic accumulation of senescent cells and their SASP can also promote tissue dysfunction, inflammation, and pathological remodeling. This can contribute to the development and progression of various age-related diseases, such as cardiovascular disease, neurodegenerative disorders, diabetes, cancer, and other conditions.

Understanding cellular senescence is therefore crucial for human health as it could lead to breakthroughs in preventing or treating these age-associated conditions, hence the NIH’s desire and willingness to develop the large-scale SenNet program.

UPMC and the University of Pittsburgh Assume Leading Roles in SenNet Project

For the SenNet project, the National Institutes of Health selected 16 teams to carry out the research, two of which are from the University of Pittsburgh and UPMC. The Pitt and UPMC teams received a combined funding of $31 million for the first five years of the project.

For the first project, Toren Finkel, MD, PhD, director of the Aging Institute at Pitt and UPMC, Distinguished Professor of Medicine, and the G. Nicholas Beckwith IIII and Dorthy B. Beckwith Endowed Chair of Translational Medicine, leads the development and research being conducted by the TriState SenNet Tissue Mapping Center. This collaborative project also involves researchers from Carnegie Mellon University, The Ohio State University, and the University of Rochester.

“We don’t know if cellular senescence is one thing or many things,” says Dr. Finkel. “An analogy is cancer: Lung cancer, pancreatic cancer, and lymphomas are all very different, even though we call them all cancer. We want to understand how senescent cells triggered by different stresses and occurring in different tissues are similar and how they are different.”

The TriState SenNet consortium’s research is focused on characterizing senescence in heart and lung cells. By conducting an in-depth comparison of different senescent cell types from various stages of the lifespan, the team hopes to discern the key indicators, biomarkers, and molecular functionality of cellular senescence in these organs.

Like molecular cartographers, the researchers will map the locations, gene expression, and protein composition in senescent cells from human heart and lung tissue slices and lab-created three-dimensional organoid models. They’ll compare different types of senescent cells from across the lifespan to characterize the biomarkers of senescence.

Collaborating with Dr. Finkel on the project is Melanie Königshoff, MD, PhD, ATSF, FERS, professor of Medicine and associate chief of Research in the Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine (PACCSM) at the University of Pittsburgh, and Oliver Eickelberg, MD, FERS, ATSF, professor of Medicine, Dorothy P. and Richard P. Simmons Endowed Chair for Pulmonary Research, and vice chair for Basic and Translational Science, also in the PACCSM Division at Pitt.

"If we can define what is different between a senescent cell and adjacent normal cells, we might be able to devise therapies that eliminate these cells based on their molecular signatures," says Dr. Königshoff. “Or, if the cell’s functionality exhibits both positive and negative characteristics, we may be able to preferentially silence the deleterious aspects of the cells while keeping their beneficial functionality intact.”

UPMC and the University of Pittsburgh, with their decades upon decades of excellence in biomedical research, along with the vast infrastructure that has been developed and deployed, and its partnerships with local and regional experts, makes it a natural fit to help lead this important new scientific endeavor that is akin to the groundbreaking Human Genome Project and the Cancer Genome Atlas Program.

“When you bring the talents and resources together from places like Pitt and CMU in Pittsburgh with their expertise in computational biology and supercomputer power, and our partners in Ohio and New York, and with the latest technological capabilities in molecular mapping, single nucleotide sequencing, spatial transcriptomics, and computational analysis deployed across our systems in recent years, it makes for a uniquely powerful partnership,” says Dr. Eickelberg.

The second SenNet project led by Pitt and UPMC will facilitate the creation, compilation, and accessibility of the vast amount of data that will be generated both by the TriState SenNet consortium and the entirety of the SenNet project, the SenNet Consortium Organization and Data Coordination Center (CODCC) will act as the program's central library. This project is guided by Jonathan Silverstein, MD, professor in the Department of Biomedical Informatics at the University of Pittsburgh and chief research informatics officer at Pitt and UPMC’s Institute for Precision Medicine.

The CODCC will annotate, organize, and ensure the reliability and standards of the data, similar to its previous successful management of The Human BioMolecular Atlas Program (HubMAP).

The CODCC, in addition to managing the SenNet Consortium, will serve the crucial role of providing computing software and hardware that will knit together SenNet’s eight tissue mapping centers and seven technology development and application projects.

Upon completion, the SenNet project’s global atlas of cellular senescence, covering diverse tissues of the human body, will be published online in an open-source repository, allowing researchers around the world to tap into this wealth of information. This will potentially pave the way for new discoveries regarding senescent cells and their role in human health, potentially leading to the development of novel therapeutic strategies.

Learn more about the NIH’s Cellular Senescent Network and the TriState SenNet Consortium led by the University of Pittsburgh.

The principal investigators of the TriState SenNET (Lung and Heart) Tissue Map and Atlas consortium (U54AG075931) are Toren Finkel, MD, PhD, and Melanie Königshoff, MD, PhD, Oliver Eickelber, MD, Pitt; Irfan Rahman, PhD. University of Rochester; and Ana Mora, MD, The Ohio State University. Other co-investigators include Mauricio Rojas, MD, The Ohio State University; and Ziv Bar-Joseph, PhD, Carnegie Mellon University.