Abstract
Cellular senescence causes irreversible growth arrest of cells. Prolonged accumulation of senescent cells in tissues leads to increased detrimental effects due to senescence associated secretory phenotype (SASP). Recent findings suggest that elimination of senescent cells has a beneficial effect on organismal aging and lifespan. In this study, using a validated replicative senescent human dermal fibroblasts (HDFs) model, we showed that elimination of senescent cells is possible through the activation of an apoptotic mechanism. We have shown in this replicative senescence model, that cell senescence is associated with DNA damage and cell cycle arrest (p21, p53 markers). We have shown that Silybum marianum flower extract (SMFE) is a safe and selective senolytic agent targeting only senescent cells. The elimination of the cells is induced through the activation of apoptotic pathway confirmed by annexin V/propidium iodide and caspase-3/PARP staining. Moreover, SMFE suppresses the expression of SASP factors such as IL-6 and MMP-1 in senescent HDFs. In a co-culture model of senescent and young fibroblasts, we demonstrated that senescent cells impaired the proliferative capacities of young cells. Interestingly, when the co-culture is treated with SMFE, the cell proliferation rate of young cells is increased due to the decrease of the senescent burden. Moreover, we demonstrated in vitro that senescent fibroblasts trigger senescent process in normal keratinocytes through a paracrine effect. Indeed, the conditioned medium of senescent HDFs treated with SMFE reduced the level of senescence-associated beta-galactosidase (SA-β-Gal), p16INK4A and SASP factors in keratinocytes compared with CM of senescent HDFs. These results indicate that SMFE can prevent premature aging due to senescence and even reprograms aged skin. Indeed, thanks to its senolytic and senomorphic properties SMFE is a candidate for anti-senescence strategies.
Highlights
Cellular senescence is a stress response induced by various stressors such as UV irradiation, pollution and replicative exhaustion
Hoechst 33342 and Dead Cell Apoptosis Kit were procured from Invitrogen (CA, USA), anti–γ-H2A.X, anti–p21CIP1, anti–cleaved caspase-3 and anti–cleaved poly (ADPribose) polymerase (PARP) antibodies, Senescence SA β-Galactosidase Staining Kit were obtained from Cell Signaling Technologies (MA, USA). 2, 2-diphenyl1-picrylhydrazyl (DPPH), L-ascorbic acid and transforming growth factor (TGF)-β human were purchased from Sigma-Aldrich (MO, USA)
Cellular senescence is accompanied by high levels of p16INK4a and/or p21CIP1, which induce cell cycle arrest, high activity of SA-β-gal, increased senescence-associated secretory phenotype (SASP) and resistance to apoptosis
Summary
Cellular senescence is a stress response induced by various stressors such as UV irradiation, pollution and replicative exhaustion. Senescence is characterized by morphological changes, high activity of senescence-associated beta-galactosidase (SA-β-gal), increase in senescence-associated secretory phenotype (SASP) characterized by cytokines and matrix metalloproteinase expression, reduction of lamin B1 expression and cytoplasmic translocation of nuclear HMGB1. The different works highlighted the importance of developing senotherapeutic approaches to selectively kill senescent cells (senolytics) or to suppress the senescence-associated secretory phenotype (SASP) driven inflammation associated with aging (senomorphics), in order to extend healthspan and potentially lifespan [11]. These findings indicate that suppression of senescent fibroblasts (senolytic approach) or mitigation of their secretory profile (senomorphic approach) are relevant targets for anti-skin aging interventions
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