Seven studies from Mayo Clinic’s Robert and Arlene Kogod Center on Aging are providing new insight into senescent cells, often called “zombie” cells because they remain active after they stop dividing. The research examines how these cells differ across tissues, why they promote chronic inflammation, and how their harmful effects might be reduced to support healthier aging.
Mapping the diversity of senescent cells
The studies investigate more than the broad link between senescent cells and aging. They examine how scientists can identify different types of senescent cells, which biological processes make them harmful, and how their effects can be controlled.
The work contributes to the Cellular Senescence Network (SenNet) consortium, a national effort funded by the National Institutes of Health Common Fund. Researchers across the United States are working to map where senescent cells occur in the body and how they change throughout a person’s life.
“This line of research advances the field of aging to precisely identify, understand, and target the specific senescent cells that contribute to age-related dysfunction. This is the foundation needed to develop new treatments that support healthy aging,” says Mayo Clinic scientist Marissa Schaefer, Ph.D., who led several of the studies in her lab.
Senescent cells are not all the same
Reliably identifying senescent cells has long been a major challenge in aging research. New findings indicate that these cells are more diverse than previously understood. Their characteristics can depend on where they are found in the body and which biological process caused them to become senescent.
To address this challenge, researchers developed the SenMayo gene set, a tool that uses patterns of gene activity to help identify senescent cells more consistently across tissues and experimental systems.
The scientists tested the approach using bone biopsies from older people. They also found that the genetic signatures became less prominent after senescent cells were removed in preclinical experiments. Since its development, SenMayo has become a widely used resource for researchers studying aging and age-related diseases.
Sandeep Khosla, MD, an endocrinologist at Mayo Clinic, was the senior author of the study “A new set of genes identifies senescent cells and predicts aging-related pathways across tissues.” Other Mayo Clinic researchers who contributed to the paper include Nathan LeBrasseur, Ph.D., Diana Jurk, Ph.D., João Passos, Ph.D., and LaTonya Hickson, MD.
The relationship between mitochondria and chronic inflammation
Other studies examined one of the most harmful features of senescent cells: their ability to produce persistent inflammatory signals.
The researchers identified additional biological processes that help explain why senescent cells continue to drive inflammation. Some involve malfunctioning mitochondria, the structures that generate most of a cell’s energy.
In one pathway, DNA and RNA released from mitochondria activate the immune response and contribute to inflammation. In another, changes in mitochondrial metabolism affect inflammatory genes through epigenetic mechanisms. These mechanisms influence whether genes are switched on or off without altering the underlying DNA sequence.
The findings suggest that future treatments might interfere with the processes that cause chronic inflammation while leaving senescent cells intact. Such an approach could complement therapies designed to destroy harmful senescent cells.
Dr. Passos was the senior author of three papers examining these mechanisms and the diversity of senescent cells:
- “Different senotypes of p16- and p21-positive cells in human and mouse aging tissues”
- “Mitochondrial metabolism and epigenetic crosstalk drive SASP”
- “Mitochondrial RNA cytosolic leakage causes SASP”
Experimental treatments target cellular aging
The Mayo Clinic team also investigated ways to reduce the number of senescent cells and limit the damage they cause. The approaches included senolytic drugs designed to eliminate senescent cells, a natural compound found in tomatoes, and genetic techniques aimed at specific populations of senescent cells.
In older mice, these interventions produced promising results. Depending on the approach, the researchers observed lower levels of inflammation and improvements in several aging-related outcomes, including physical frailty, inflammation in the brain, and performance on cognitive tasks.
Another study identified IL-23R as a potential biomarker that could eventually help researchers measure aspects of biological aging through blood tests. The marker may help assess age-related changes and determine whether future treatments are working.
These findings are still preliminary as they relate to medical applications. Further research is needed to establish whether the approaches are safe and effective in humans. The experiments nevertheless offer clues for developing treatments that target the cellular processes involved in age-related diseases more precisely.
Dr. Schaefer was the lead author of two studies examining biomarkers and potential interventions:
- “IL-23R is a biomarker of aging-related circulatory and tissue aging.”
- “Spatial mapping and senolytic targeting of aging and disease-related microglia in the brain white matter of aged mice”
New directions for healthy aging research
Together, the seven studies reflect a shift in the way scientists approach cellular aging. Rather than focusing only on the general observation that senescent cells contribute to age-related decline, researchers are identifying which populations cause the greatest problems, what makes them harmful, and how their specific effects can be controlled.
The findings also challenge the idea that eliminating senescent cells should always be the first treatment strategy. By understanding the molecular pathways behind persistent inflammation, researchers may be able to block harmful signals without removing the cells that produce them.
Mayo Clinic researcher Darren Baker, Ph.D., was the senior author of “Senotypes define diverse landscapes of senescent cells,” a paper examining the different characteristics of senescent cell populations.
The work also supports Mayo Clinic’s broader PreCure research initiative, which aims to give doctors better ways to identify and address harmful biological changes before they develop into diseases or difficult-to-treat conditions.
By showing how senescent cells differ, why they promote inflammation, and which processes may be targeted, the research provides a more detailed roadmap for future treatments intended to support healthier aging.
Source: www.sciencedaily.com
