Mayo Clinic Studies Map Why 'Zombie' Aging Cells Differ and How Their Harm Might Be Curbed

Seven studies from Mayo Clinic's Robert and Arlene Kogod Center on Aging, published in Nature journals, take on a question that has dogged aging research for years: if senescent cells, the so-called zombie cells that linger in the body and feed inflammation and disease, are a problem, which ones are, and what exactly makes them harmful?

The answer the papers give is that these cells are not one thing. Reliably identifying senescent cells has long been a major obstacle, and the new work shows they are far more varied than previously understood. Their characteristics depend on where they sit in the body and on which biological process pushed them into senescence in the first place.

To make them easier to spot, the team developed a tool called the SenMayo gene set, which uses patterns of gene activity to identify senescent cells more consistently across tissues and experimental systems. The researchers tested it on bone biopsies from older adults, and they found the signature faded after senescent cells were removed in preclinical experiments. Sundeep Khosla, M.D., a Mayo Clinic endocrinologist, was senior author of that study. Since its release, SenMayo has become a widely used resource in research on aging and related diseases. Darren Baker, Ph.D., was senior author of a further paper, "Senotypes define the diverse landscape of senescent cells," which examines the varied characteristics of these populations.

Other studies in the set looked at why the cells generate chronic inflammation. Several of the mechanisms involve malfunctioning mitochondria, the structures that produce much of a cell's energy. In one pathway, DNA and RNA that leak from mitochondria trigger immune responses that drive inflammation. In another, changes in mitochondrial metabolism alter inflammatory gene activity through epigenetic mechanisms, which switch genes on or off without changing the DNA sequence. João Passos, Ph.D., was senior author of three papers on these mechanisms and on the diversity of senescent cells, including "Mitochondrial RNA cytosolic leakage drives the SASP."

That finding opens a different line of attack. Researchers may eventually be able to interrupt the processes behind chronic inflammation while leaving the senescent cells intact, rather than trying to destroy every harmful aging cell.

The team also tested ways to reduce senescent cells or limit their damage: senolytic drugs designed to eliminate them, a natural compound found in tomatoes, and genetic techniques aimed at particular populations of aging cells. In older mice, depending on the approach, researchers saw lower inflammatory measures and improvements in physical frailty, brain inflammation and performance on cognitive tasks. Marissa Schafer, Ph.D., whose laboratory directed several of the investigations, was lead author of two studies, one on mapping and targeting disease-associated microglia in the white matter of aged mouse brains. The other identified IL-23R as a possible blood-based biomarker of aging, which might one day help gauge aging-related changes and show whether a treatment is working.

The results remain preliminary. Whether any of these approaches is safe and effective in people has not been established and will take more research.

The work also feeds into the Cellular Senescence Network (SenNet) Consortium, a nationwide effort funded by the National Institutes of Health Common Fund to map where senescent cells occur in different human tissues and how they change over a lifetime. It supports Mayo Clinic's Precure Research initiative as well, which aims to give physicians better ways to catch harmful biological changes before they become disease. Schafer describes the work as groundwork for therapies that support healthy aging. What to watch next is whether the IL-23R biomarker and the targeted approaches hold up outside the mouse.