by Justin Jackson , Medical Xpress

RNAscope of p16ink4a (green), Il23r (red), and Cd3e (cyan) from young (top, 2 mo.) and old (bottom, 24 mo.) kidney tissue from mice on p16-InkAttac background. DAPI nuclear stain is depicted in dark blue. Old kidney exhibits dense and perivascular Cd3e + Il23r+ immune nodes. Credit: Nature Aging (2024). DOI: 10.1038/s43587-024-00752-7

Mayo Clinic researchers have identified interleukin-23 receptor (IL-23R) as a significant biomarker of cellular senescence and aging in both mice and humans. Experiments show that IL-23R levels in the bloodstream increase with age and can decrease, reflecting senescent cell clearing, with senolytic therapies.

Cellular senescence occurs when cells stop dividing but do not trigger apoptosis mechanisms that would allow them to die naturally. Instead, they are stuck in a zombie-like state, where they still have the urge to feed and carry out metabolic activities, but with increasingly incoherent cell signaling and increased pro-inflammatory cytokine secretions.

Senescent cell activity has been linked to several age-related diseases, including those of the immune, cardiovascular, metabolic, pulmonary, musculoskeletal and neurological systems.

Scientists have been searching for a biomarker that reliably estimates the levels of active senescent cells in the body. If found, this biomarker could inform clinical interventions, potentially intervening before disease conditions present themselves.

In the study “IL-23R is a senescence-linked circulating and tissue biomarker of aging,” published in Nature Aging, researchers sought to identify senescence-related biomarkers and measure their responsiveness to different therapeutics in mice of various ages.

The team tested 92 plasma proteins through the Olink Target 96 Mouse Exploratory panel and ultimately analyzed 67 (25 were excluded due to low or no detection).

Tissues, including kidney, liver, spleen, cerebral cortex, adipose and lung, were examined with real-time PCR for 21 gene expressions related to senescence secretions and inflammation markers.

Applying short-term interventions with drugs that clear senescent cells, including venetoclax, navitoclax, fisetin and luteolin, as well as transgenic clearance methods targeting p16-positive senescent cells, mice were examined for changes in plasma proteins and tissue transcripts.

Analyses showed that three of the tested plasma proteins, IL-23R, CCL5 and CA13, displayed age-related alterations in circulation and tissues, indicating potential biomarker marker viability.

Age-dependent increases in IL-23R and CCL5 were reversed by senolytic treatment, and CA13 levels, which normally decline with age, were restored to more youthful levels.

Researchers identified IL-23R as the most promising plasma protein biomarker due to its obvious and consistent association with aging across multiple tissue parameters. IL-23R increased with age in both mice and humans and had a robust change response to senolytic interventions.

The strong correlation between IL-23R and other well-defined senescence tissue markers makes it a potential reliable biomarker of systemic senescent cell burden, offering an important new tool for probing and possibly preventing age-related diseases.

More information: Chase M. Carver et al, IL-23R is a senescence-linked circulating and tissue biomarker of aging, Nature Aging (2024). DOI: 10.1038/s43587-024-00752-7

Journal information:Nature Aging

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