Senescent Cell Tissue Mapping Will Facilitate Study of Aging and Chronic Diseases

UConn Health and The Jackson Laboratory for Genomic Medicine assume key roles, share in $13.5 million NIH grant with top medical centers

Researchers at the UConn Center on Aging at UConn Health and The Jackson Laboratory for Genomic Medicine (JAX) in Farmington, in collaboration with fellow investigators at several major health and research institutions, have received funding from the National Institutes of Health (NIH) to participate in a study of rare types of cells, called senescent cells, that play significant roles in biological processes related to aging. This $13.5-million award (U54 AG075941) is titled the KAPP-Sen Tissue Mapping Collaborative, given the investigators’ focus on studies seeking to map senescent cells in human kidneys, adipose tissues, pancreas, and placenta.

The ability of human cells to divide into two represents a fundamental feature of development that continues in some cases throughout an individual’s life. However, in a series of seminal studies conducted in the 1960s, Dr. Leonard Hayflick showed that normal cells can undergo only a limited number of divisions before they stop dividing and enter a state of replicative senescence.

More recent research has shown that such seemingly dormant senescent cells are far from benign, and in fact play important roles in health as drivers of many different chronic diseases, either directly or through the release of molecules that may affect both neighboring and distant cells. As a result, senescent cells are increasingly believed to also contribute to the onset and progression of multiple varied chronic diseases and conditions of aging such as cardiovascular diseases, osteoporosis, frailty, and neurodegeneration.

Dr. George Kuchel

“Cellular senescence represents one of the major biological hallmarks of aging,” says Dr. George Kuchel, director, UConn Center on Aging at UConn Health, and a principal investigator on the U54-funded project. “Use of animal models of aging and chronic diseases has greatly advanced our understanding of cellular senescence and has led to the discovery of compounds called senolytics, which allow senescent cells to die and be cleared by the body, resulting in significant functional improvements.”

Given these very promising animal studies, Kuchel adds, many of these interventions are now at the point of entering human proof-of-concept clinical trials, while others are at various stages of preclinical testing.

“In spite of this remarkable progress,” Kuchel reflects, “very little is known as to the presence, precise nature and relevance of senescent cells in human tissues, especially in the absence of overt diseases. We realized we could make a significant contribution here at UConn and through our research partners at JAX, but this was too big to handle ourselves – we needed to work closely with several surgical centers, including transplant leaders, to ensure the robust human tissue pipeline needed to make real research progress.”

The senescence mapping research they are conducting, Kuchel explains, comprises four types of tissues, including healthy samples from human kidneys, pancreas, placenta and fat tissue. Team members around the country, he says, will collect these samples as part of surgery and transplant procedures, and ship them to Farmington, where the tissues will be catalogued and analyzed, and results posted to the national database.

“This grant is an enormous and critically important step for better understanding the mechanics of senescent cells,” says Kuchel. “Single-cell analysis allows us to take and separate the cells from within tissue to examine properties of each cell in detail, ‘mapping’ each component to more thoroughly understand how they work, and in time, develop medicines that will limit their negative effects and accentuate their positive properties. The NIA Translational Geroscience Network, for which UConn is one of eight founding institutions, is currently supporting more than 40 clinical trials testing such compounds in humans. However, this grant will help propel the field in new directions.”

Research collaborators include the Joslin Diabetes Center, Brigham and Women’s Hospital in Boston, the Mayo Clinic in Rochester, Minnesota, and the University of Texas Health Science Center at San Antonio.

The NIH Common Fund is providing $125 million in funding 16 grants over five years, including eight awards for the creation of SenNet Tissue Mapping Centers, which includes UConn Health, JAX, and their project partners. The Tissue Mapping Centers will identify biomarkers of senescent cells in humans and then construct high-resolution, detailed maps of cellular senescence across the lifespan and physiological states, which will be shared through a national SenNet database, creating a publicly accessible and searchable Atlas of Cellular Senescence. The SenNet program is a trans-NIH effort managed collaboratively by staff from the NIH Common Fund, the National Institute on Aging, and the National Cancer Institute.

Kuchel is the lead/contact multiple principal investigator (PI). The team comprises other multiple PIs including Paul Robson at The Jackson Laboratory for Genomic Medicine; Dr. Nicolas Musi at the University of Texas Health Science Center at San Antonio; and Dr. Vesna Garovic at the Mayo Clinic.

It also involves many co-investigators including Dr. Stefan Tullius at the Brigham and Women’s Hospital; Dr. Cristina Aguayo-Mazzucato at Joslin Diabetes Center, an affiliate of Harvard Medical School; and Ming Xu at the UConn Center on Aging at UConn Health. Additional contributors in Farmington include Dr. Qian Wu in the Department of Pathology and Laboratory Medicine, who will be responsible for pathological tissue analysis, as well as Duygu Ucar  and Jeff Chuang from JAX, who together with Chia-Ling Kuo from UConn Health will conduct data analysis.