*3.10. Senescence*

Senescence is defined the condition or process of deterioration with age [177]. Senescence plays a role in multiple biological events, such as embryogenesis, tissue regeneration and repair, ageing, cardiovascular, renal, liver diseases, and cancer [178,179]. EGCG has been implicated in senescence in di fferent works. For example human mesenchymal stem cells (hMSCs) show the peculiar behavior of producing abundant ROS during culturing and this issue has been exploited with a natural anti-oxidant as EGCG [180]. The work explored the anti-senescent e ffect of EGCG in H2O2-exposed hMSCs and proved that EGCG reversed oxidative stress by downregulating the p53–p21 signaling pathway and upregulating Nrf2 expression. Similarly, in primary cells, including rat vascular smooth muscle cells (RVSMCs), human dermal fibroblasts (HDFs) and human articular chondrocytes (HACs), the same concentrations of EGCG (50 or 100 μM) could prevent senescence and recover cell cycle progression, again impacting on the p53 pathway at least in HDFs cells [181]. Furthermore, in 3T3-L1 preadipocytes, EGCG could inhibit stress-induced senescence (H2O2-induced) by countering DNA damage and cell cycle arrest [182]. In this work, EGCG (same concentrations as above, 50 or 100 μM) modulated PI3K/Akt/mTOR and AMPK pathways by blocking ROS, iNOS, Cox-2, NF-kB, and p53, and increasing apoptosis by suppressing antiapoptotic protein Bcl-2. Moreover, in WI-38 fibroblasts at late-stage (population doubling > 25) used as model of oxidative stress and inflammation, EGCG (25, 50, 100 μM) reduced TNFα, IL-6, ROS, again acting on p53 [183]. ECGC also decreased retinoblastoma expressions, while enhancing E2F2 expressions and superoxide dismutase (SOD) 1 and 2, all being implicated in oxidation processes. EGCG has been shown to a ffect the development and severity of cellular senescence, but from a therapeutic perspective more work is needed. Senolytic attributes of EGCG are interesting, especially for attenuating age-associated disorders, though clinical trails and health consequence still need to be proposed and discovered.
