Seven studies from Mayo Clinic researchers are providing new insight into senescent cells, sometimes called “zombie” cells because they remain active after they stop dividing. These cells release inflammatory substances linked to age-related diseases, and the research examines how different types can be identified, why they cause persistent inflammation, and how their effects might be reduced.
Mapping the diversity of senescent cells
The studies were conducted by scientists at Mayo Clinic’s Robert and Arlene Kogod Center on Aging. Rather than simply confirming that senescent cells are involved in aging, the research investigates how these cells differ across tissues, what makes them harmful, and how their effects can be targeted.
The work also contributes to a national effort to create a detailed map of senescent cells throughout the human body. The Cellular Senescence Network, or SenNet, brings together researchers from across the United States and is funded by the National Institutes of Health Common Fund. Its goal is to document where senescent cells occur in different tissues 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.
Zombie cells are not all the same
Reliably identifying senescent cells has long been a major challenge for scientists studying aging. The new research shows that these cells are more diverse than previously understood. Their characteristics depend on where they are located in the body and which biological process caused them to become senescent.
To address this challenge, researchers developed a tool called the SenMayo gene set. It uses patterns of gene activity to identify senescent cells more consistently across tissues and experimental systems.
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 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 characteristics of senescent cells: their tendency to cause ongoing inflammation.
Researchers identified additional biological processes that may explain why these cells continue to produce inflammatory signals. Some of the processes 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. Another involves changes in mitochondrial metabolism that influence inflammatory genes through epigenetic mechanisms. These mechanisms affect whether genes are switched on or off without changing the underlying DNA sequence.
The findings suggest that researchers may eventually be able to interfere with the processes that cause chronic inflammation while leaving the senescent cells intact. This could provide an alternative to treatments that attempt to destroy harmful senescent cells.
Dr. Passos was the senior author of three papers investigating 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 cell 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 that target specific populations of senescent cells.
When tested in older mice, these interventions produced promising results. Depending on the approach, researchers observed reductions in measures of inflammation and improvements in several aging-related outcomes, including physical frailty, brain inflammation, and performance on cognitive tasks.
Another study identified a potential way to measure aspects of biological aging through blood tests. Researchers identified IL-23R as a possible biomarker that could eventually help scientists assess age-related changes and determine whether future treatments are effective.
These results remain preliminary as they relate to medical applications. Further research is needed to determine whether the approaches are safe and effective in humans. Nevertheless, the experiments provide clues for developing treatments that more precisely address the cellular processes involved in age-related diseases.
Dr. Schaefer was the lead author of two studies examining biomarkers and possible 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 how scientists approach cellular aging. Researchers are moving beyond the broad observation that senescent cells contribute to age-related deterioration. They are now working to identify which cell 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 that cause persistent inflammation, researchers may be able to block harmful signals without eliminating the cells that produce them.
Mayo Clinic researcher Darren Baker, Ph.D., was the senior author of the paper “Senotypes define diverse landscapes of senescent cells,” which examined the different characteristics of senescent cell populations.
The research also supports Mayo Clinic’s broader PreCure initiative. The program aims to give doctors better ways to identify and intervene in 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 studies provide a more detailed roadmap for future treatments intended to support healthier aging.
Source: www.sciencedaily.com