Mallotus japonicus leaf extract restores TRPM6 magnesium channel expression and suppresses cellular senescence in colonic epithelial cells.

Age-related alterations in intracellular Mg2+ homeostasis can influence cellular bioenergetics and stress responses, yet the epithelial mechanisms linking aging and cellular senescence to impaired magnesium handling remain incompletely defined. Frailty is an emerging public health challenge in aging societies, and age-related magnesium deficiency has been proposed as one contributing factor. We investigated whether aging and cellular senescence impair epithelial magnesium handling in the colon and whether Mallotus japonicus (M. japonicus) leaf extract ameliorates these alterations in mouse colonic epithelial MCE301 cells under senescence-inducing conditions. The mRNA levels of transient receptor potential melastatin 6 (TRPM6) magnesium channel were decreased in the intestines of middle-aged mice and in MCE301 cells after long-term culture or tenovin-6-induced senescence. TRPM6 knockdown, tenovin-6, an inducer of cellular senescence, and low-Mg2+ medium each lowered intracellular free Mg2+ concentration ([Mg2+]i). Low-Mg2+ medium also attenuated proliferation. Transcriptome profiling suggested mitochondrial involvement under Mg2+-limiting conditions, consistent with reduced mitochondrial membrane potential and ATP production as well as increased mitochondrial fragmentation. M. japonicus leaf extract restored TRPM6 expression and [Mg2+]i, improved mitochondrial function, and suppressed senescence-associated secretory phenotype-related gene expression. Among the tested components of M. japonicus leaf extract, geraniin showed the strongest activity and also reduced senescence-associated β-galactosidase-positive cells, whereas corilagin, mallotinic acid, and mallotusinic acid showed partial effects. We suggest that aging- and senescence-associated TRPM6 downregulation is linked to impaired magnesium homeostasis and mitochondrial dysfunction in colonic epithelial cells. M. japonicus leaf extract and selected ellagitannin-related polyphenols mitigate these senescence-associated alterations.