In the years since the first demonstration that clearance of senescent cells produces rejuvenation in old mice, and the first programs to develop senolytic drugs that can selectively destroy senescent cells, ever more research has been directed into better understanding the distinctive biochemistry of senescent cells. Any novel feature could turn out to be the basis for a better senolytic drug, or a way to suppress the inflammatory signaling of senescent cells. Here, for example, researchers focus on the relevance of one specific aspect of RNA processing in cells that appears relevant to senescence.
m6A (N6-methyladenosine) RNA modification has emerged as a key regulator of cellular processes, including senescence. m6A is the most prevalent internal modification in eukaryotic mRNA and is dynamically regulated by "writers" (methyltransferases, such as METTL3 and METTL14), "erasers" (demethylases, such as FTO and ALKBH5), and "readers" (m6A-binding proteins, such as YTHDF1 and YTHDC1). By modulating RNA stability, splicing, translation, and decay, m6A modifications influence a wide array of biological functions, including cell proliferation, differentiation, and stress responses. Recent studies have highlighted the role of m6A in regulating the pathways associated with cellular senescence, including p53, NF-κB, and senescence-associated secretory phenotype (SASP) components. However, the intricate interplay between m6A modifications and senescence remains incompletely understood, warranting further exploration.
While targeting m6A modifications holds great potential for senescence therapy, several limitations and challenges must be addressed before its clinical translation. First, the dynamic and reversible nature of m6A modifications, mediated by "writers" (methyltransferases), "erasers" (demethylases), and "readers" (binding proteins), adds significant complexity to their regulation. Targeting these components may lead to off-target effects due to the widespread role of m6A in various cellular processes beyond senescence, such as stem cell maintenance, immune responses, and tumor progression. This non-specificity could result in unintended disruptions to normal physiological functions. Furthermore, the heterogeneity in senescence mechanisms across cell types and tissues complicates the development of universal m6A-targeted therapies. A therapy effective in one cellular context may exhibit limited efficacy or even adverse effects in another.
Finally, the detection and quantification of m6A modifications remain challenging due to the lack of standardized and highly sensitive tools. Current techniques, such as m6A-seq, provide valuable insights but have limitations in resolution and scalability. Without precise detection methods, identifying specific m6A targets for therapeutic intervention is difficult, which hinders progress in the field. Developing small molecules or RNA-based therapeutics targeting m6A modulators poses challenges related to specificity and toxicity. Ensuring efficient delivery to senescent cells while avoiding off-target effects in non-senescent cells remains a major hurdle. Advanced delivery systems, such as nanoparticle-based or cell-specific delivery platforms, are needed but require further optimization for clinical use. Overcoming these limitations requires a multidisciplinary approach, integrating advances in molecular biology, bioinformatics, drug delivery systems, and clinical research. Continued efforts to refine m6A-targeted strategies and deepen our understanding of m6A's role in senescence will pave the way for safer and more effective therapies.
Link: https://doi.org/10.3389/fimmu.2025.1534263
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