A series of Mayo Clinic studies is helping reshape scientists' understanding of senescent, or "zombie," cells - aging cells that no longer divide but remain metabolically active and release inflammatory molecules that contribute to age-related diseases.
Published across Nature journals, the studies authored by scientists within the Robert and Arlene Kogod Center on Aging move the field beyond recognizing that senescent cells contribute to aging. Together, they provide new tools to identify these cells, uncover mechanisms that drive inflammation and explore strategies to reduce their effects in preclinical models. In collaboration with researchers across the U.S., they are part of an ambitious project to map senescent cells across different tissues. The project is called the Cellular Senescence Network (SenNet) Consortium and is funded by the National Institutes of Health Common Fund. Its primary objective is to compile comprehensive atlases of senescent cells within the human body over a lifetime.
"This body of work is moving the aging field forward to precisely identify, understand and target the specific senescent cells that contribute to age-related dysfunction, which is the necessary groundwork to develop new therapies that support healthy aging," says Marissa Schafer, Ph.D., a Mayo Clinic researcher whose laboratory led several of the studies.
Exploring new therapeutic strategies
Several studies evaluated approaches designed to reduce the burden or harmful effects of senescent cells in preclinical models.
The research examined interventions, including senolytic drugs, a naturally occurring compound found in tomatoes, and genetic approaches that selectively target senescent cells. In aged mice, these strategies reduced measures of inflammation and improved outcomes associated with aging, including physical frailty, brain inflammation and cognitive performance.
Another study identified IL-23R as a potential blood biomarker that could one day help researchers assess biological aging and monitor responses to future therapies.
Although additional research is needed before these findings can be translated to patient care, the studies provide a stronger scientific foundation for developing more targeted interventions for age-related diseases.
Dr. Schafer is the senior author of the following papers:
- "IL-23R is a senescence-linked circulating and tissue biomarker of aging"
- "Spatial mapping and senolytic targeting of senescent and disease-associated microglia in aged mouse brain white matter"
Revealing why senescent cells drive inflammation
Additional studies uncovered previously unknown mechanisms that help explain why senescent cells produce persistent inflammation.
Researchers found that dysfunctional mitochondria - the structures that generate energy inside cells - contribute to inflammation through multiple pathways. One mechanism involves mitochondrial DNA and RNA activating immune signaling. Another shows that mitochondrial metabolism changes how inflammatory genes are activated through epigenetic regulation.
Together, these discoveries identify potential therapeutic targets that could reduce harmful inflammation without necessarily eliminating senescent cells.
João Passos, Ph.D., is the senior author of the following papers:
- "Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues"
- "Mitochondrial metabolism and epigenetic crosstalk drive SASP"
- "Mitochondrial RNA cytosolic leakage drives the SASP"
A growing body of research
Taken together, these studies advance the field from demonstrating that senescent cells contribute to aging toward understanding which senescent cells matter most, how they drive disease and how they may be targeted more precisely.
Rather than focusing solely on eliminating senescent cells, the research supports a more nuanced approach that aims to identify the biological pathways responsible for harmful inflammation and develop therapies that selectively interrupt those processes.
Darren Baker, Ph.D., a Mayo Clinic researcher, is the senior author of the paper, "Senotypes define the diverse landscape of senescent cells."
The research is part of a larger effort at Mayo Clinic called the Precure Research initiative, which is focused on developing tools that empower clinicians to predict and intercept biological processes before they evolve into disease or progress into complex, hard-to-treat conditions.
Review the studies for a complete list of authors, disclosures and funding.
