Abstract
Immunosenescence, the age-associated decline in immune function, is accompanied by altered
macrophage phenotypes and increased chronic inflammation. Here, we examined the role of the
mitochondrial RNA-binding protein GRSF1 in regulating macrophage-driven inflammation and
its impact on neighboring fibroblasts. We found that macrophages differentiated from GRSF1-
deficient THP-1 monocytes, particularly M(IL-4+IL-13) macrophages, displayed elevated IL6 mRNA
expression levels and TNF-α secretion, without inducing overt senescence in macrophages themselves.
Conditioned media from these macrophages triggered robust senescence-associated transcriptional
changes in fibroblasts, including increased expression of IL6, TNF, DPP4, and IL8, as well as elevated
SA-β-gal activity. Notably, expression of NF-κB-regulated long noncoding RNAs, such as ANRIL and
PACER, was also induced in fibroblasts, suggesting the engagement of an NF-κB-linked inflammatory
program. These transcriptional responses were mitigated by red ginseng extract, an anti-inflammatory
compound known to suppress TNF-α signaling. Collectively, our findings suggest that GRSF1 depletion
in macrophages contributes to a paracrine inflammatory niche that promotes senescence-associated
gene expression in surrounding cells.