Epigallocatechin gallate suppresses premature senescence of preadipocytes by inhibition of PI3K/Akt/mTOR pathway and induces senescent cell death by regulation of Bax/Bcl-2 pathway.
The phytochemical epigallocatechin gallate (EGCG) has been reported to alleviate age-associated immune disorders and organ dysfunction. However, information regarding the mechanistic role of EGCG in the suppression of cellular senescence is limited. The present study thus assessed the effects and underlying mechanisms of EGCG in the inhibition of senescence as well as its potential to selectively eliminate senescent cells (senolytics) using 3T3-L1 preadipocytes. Premature senescence was established in cells by repeated exposure of H2O2 at a sub-lethal concentration (150 μM). H2O2 treated cells showed characteristic senescence-associated features including increased cell size, senescence-associated β-galactosidase activity (SA-β-gal), development of senescence-associated secretory phenotype (SASP), activation of reactive oxygen species (ROS) and pathways, DNA damage as well as induction of cell cycle inhibitors (p53/p21WAF1/p16INK4a). In addition, a robust activation of PI3K/Akt/mTOR and AMPK pathways was also observed in H2O2 treated cells. Presence of EGCG (50 and 100 μM) showed significant downregulation of PI3K/Akt/mTOR and AMPK signaling along with the suppression of ROS, iNOS, Cox-2, NF-κB, SASP and p53 mediated cell cycle inhibition in preadipocytes. In addition, EGCG treatment also suppressed the accumulation of anti-apoptotic protein Bcl-2 in senescent cells thereby promoting apoptosis mediated cell death. Our results collectively show that EGCG acts as an mTOR inhibitor, SASP modulator as well as a potential senolytic agent thereby indicating its multi-faceted attributes that could be useful for developing anti-aging or age-delaying therapies.
['Kumar|Ravi|R|', 'Sharma|Anamika|A|', 'Kumari|Amita|A|', 'Gulati|Ashu|A|', 'Padwad|Yogendra|Y|', 'Sharma|Rohit|R|0000-0001-6209-3845']
D019588:Aging, Premature D000975:Antioxidants D017209:Apoptosis D002392:Catechin D059447:Cell Cycle Checkpoints D049109:Cell Proliferation D016922:Cellular Senescence D006801:Humans D017382:Reactive Oxygen Species D015398:Signal Transduction D058570:TOR Serine-Threonine Kinases
Senescence MTOR EGCG Senolytic ROS