Terpenes: natural compounds found in plants as potential senotherapeutics targeting senescent mesenchymal stromal cells and promoting apoptosis

Background: Senescence in stem cells and progenitor cells can be particularly detrimental because these cells are essential for tissue renewal and overall organismal homeostasis. In mesenchymal stromal cells (MSCs), which comprise a heterogeneous mix of stem cells, progenitors, fibroblasts, and other stromal cells, senescence poses a significant challenge, as it impairs their ability to support tissue repair and maintenance. This decline in regenerative capacity can contribute to aging-related diseases, impaired wound healing, and degenerative disorders. One hallmark of senescence is resistance to apoptosis, mediated by activation of anti-apoptotic pathways. Consequently, senotherapeutics have emerged as a promising strategy to selectively eliminate senescent cells and promote healthy aging. Plant secondary metabolites, notably polyphenols and terpenes, exhibit diverse effects on living organisms and have served as medicinal agents. Methods: In this study, we investigated four terpenes—carvacrol, thymol, eugenol, and lycopene—for their senolytic potential in human senescent MSCs. Results: We found that these compounds induce apoptosis through both caspase-dependent and caspase-independent mechanisms, involving the activation of BAX, cytochrome c release, and translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei. Importantly, terpene-induced apoptosis was associated with a significant increase in reactive oxygen species, and pre-incubation with glutathione partially rescued cell viability, confirming oxidative stress as a central trigger. Moreover, we identified SRC pathway modulation as a critical determinant of the senescence-to-apoptosis shift, highlighting a key regulatory switch in terpene action. Conclusions: These findings provide a detailed mechanistic dissection of terpene-induced senolysis and underscore their potential as promising candidates for senotherapeutics targeting senescent cells.