GLS1 expression and its role in mesenchymal stem cell aging and metabolic reprogramming

Mesenchymal stem cells (MSCs) possess the ability to differentiate into various cell types,?facilitating the repair of damaged tissues and organs while enhancing their functions, thereby playing a role in healing age-related decline. However, MSCs are also subject to aging, leading to a significant reduction in their self-renewal capacity and differentiation potential. We observed a marked increase in cell size among aged MSCs, with GLS1 expression levels in these enlarged cells being significantly higher compared to those in normal cells. Inducing cellular aging with D-galactose further elevates GLS1 expression and is accompanied by an increase in cell size. Moreover, GLS1 overexpression may enhance the expression of key glycolytic enzymes through the upregulation of FOXK2, leading to metabolic reprogramming. Conversely, overexpressing GLS1 in normal cells does not directly elevate the expression of aging-related markers, nor does it impede cell proliferation. However, GLS1 overexpression appears to diminish differentiation potential by inhibiting the Wnt/β-Catenin signaling pathway. Thus, inhibited differentiation ability of senescent MSCs, which expressed higher GLS1, may be a protective mechanism for the body to prevent the risk on newly generated tissue after the differentiation. This study investigates the relationship between GLS1 and aging, proposing that GLS1 could serve as a potential biomarker for assessing MSC quality, thereby minimizing differences in effects during MSCs-based therapy. Furthermore, elucidating the association between GLS1 and MSC senescence is crucial for advancing our understanding of the intricate mechanisms underlying MSC aging.