The study of aging and its biological underpinnings has gained immense attention in recent years due to the profound implications for human health, particularly with age-related diseases such as cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. One of the key phenomena associated with aging is cellular senescence, a state in which cells cease to divide but remain metabolically active, often contributing to chronic inflammation and tissue dysfunction. Understanding the markers and mechanisms of senescence is crucial to developing therapeutic strategies that could slow, halt, or even reverse aspects of aging. Recent groundbreaking research from Mayo Clinic researchers has identified the interleukin-23 receptor (IL-23R) as a potential biomarker for cellular senescence and aging, shedding light on its role in the aging process and its potential in clinical interventions.
Cellular senescence is a natural cellular response to various stressors, including DNA damage, oxidative stress, and telomere shortening. When cells enter a state of senescence, they stop dividing but do not undergo apoptosis (programmed cell death). Instead, these cells adopt a “zombie-like” state, remaining metabolically active but unable to contribute to tissue function as they once did. Senescent cells secrete a variety of pro-inflammatory cytokines, growth factors, and proteases, collectively referred to as the senescence-associated secretory phenotype (SASP). The SASP is thought to contribute to aging and age-related diseases by inducing chronic inflammation and disrupting tissue function. In addition, senescent cells accumulate in tissues over time, further exacerbating age-related dysfunction.
As the body ages, the accumulation of senescent cells becomes increasingly problematic. These cells are linked to a variety of age-related diseases, including cardiovascular disease, neurodegenerative disorders, metabolic dysfunction, and musculoskeletal decline. The persistent inflammation driven by senescent cells is believed to be a key factor in the development of these diseases. Thus, scientists have been searching for a reliable biomarker that could measure the burden of senescent cells in the body, providing a tool for early detection and intervention before age-related diseases manifest in full force. If a biomarker for senescence could be identified, it could serve as a valuable diagnostic and prognostic tool, offering clinicians a way to intervene early in the aging process and potentially delay or prevent the onset of related diseases.
In the study “IL-23R is a senescence-linked circulating and tissue biomarker of aging,” published in Nature Aging, Mayo Clinic researchers investigated potential biomarkers of senescence by analyzing plasma proteins and tissue samples from mice of various ages. The researchers aimed to identify biomarkers that could reliably reflect the levels of active senescent cells in the body and measure their responsiveness to therapeutic interventions. This is a crucial step in advancing the field of aging research, as it would allow for more accurate assessments of the effectiveness of anti-aging therapies, including those aimed at clearing senescent cells.
To identify promising biomarkers, the research team tested 92 plasma proteins using the Olink Target 96 Mouse Exploratory panel, ultimately analyzing 67 proteins after excluding those with low or no detection. Additionally, the researchers examined various tissues—such as the kidney, liver, spleen, cerebral cortex, adipose tissue, and lung—using real-time PCR to measure the expression of genes related to senescence and inflammation. The study involved both young and old mice, allowing the researchers to observe age-dependent changes in plasma proteins and tissue gene expression.
The study tested several senolytic drugs, which are compounds designed to selectively target and eliminate senescent cells. Among the drugs tested were venetoclax, navitoclax, fisetin, and luteolin. These senolytic agents have shown promise in preclinical studies for their ability to clear senescent cells and improve age-related health outcomes. The team also used transgenic methods to clear p16-positive senescent cells, a well-established marker of cellular senescence. After applying these interventions, the researchers monitored changes in plasma protein levels and tissue gene expression to assess the impact of senolytic treatments on aging biomarkers.
The analysis revealed that three of the tested plasma proteins—IL-23R, CCL5, and CA13—exhibited age-related changes in their levels, both in circulation and in tissues. These proteins appeared to be associated with cellular senescence and aging, making them potential biomarkers for assessing senescent cell burden. Notably, IL-23R and CCL5 levels increased with age, while CA13 levels typically declined with age. These changes were reversible with senolytic treatments, highlighting the potential for using these biomarkers to monitor the effectiveness of therapies aimed at clearing senescent cells.
Among the three proteins, IL-23R emerged as the most promising biomarker. IL-23R is a receptor involved in the immune response and inflammation, and its levels were found to be consistently elevated in both the plasma and tissues of aged mice. Furthermore, IL-23R levels showed a robust response to senolytic interventions, with a clear decrease in its levels following treatment with drugs that target senescent cells. The strong correlation between IL-23R and other established markers of cellular senescence further supports its potential as a reliable biomarker for systemic senescent cell burden.
The identification of IL-23R as a senescence-linked biomarker has significant implications for the field of aging research. By monitoring IL-23R levels, researchers and clinicians may be able to assess the effectiveness of senolytic therapies and track changes in the body’s senescent cell population over time. This could enable earlier detection of age-related diseases and allow for more personalized interventions to slow the aging process. Moreover, the discovery of IL-23R as a biomarker opens the door for further research into its role in aging and inflammation, potentially uncovering new therapeutic targets for age-related diseases.
The ability to measure and monitor cellular senescence in humans is a major step toward understanding the complex biology of aging. While the study primarily involved mice, the researchers found that IL-23R levels also increased with age in humans, suggesting that the biomarker may have broad applicability across species. If further studies confirm these findings in human populations, IL-23R could become a critical tool for diagnosing and treating age-related conditions, particularly those linked to chronic inflammation and tissue dysfunction caused by senescent cells.
Reference: 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