Long-term consumption of green tea EGCG enhances murine health span by mitigating multiple aspects of cellular senescence in mitotic and post-mitotic tissues, gut dysbiosis, and immunosenescence

Abstract

Cellular senescence is emerging as a major hallmark of aging, and its modulation presents an effective anti-aging strategy. This study attempted to understand the progression of cellular senescence in vivo, and whether it can be mitigated by chronic consumption of green tea catechin epigallocatechin gallate (EGCG). We profiled cellular senescence in various organs of mice at four different time-points of lifespan, and then explored the influence of EGCG consumption in impacting markers of cellular senescence, inflamm-aging, immunosenescence, and gut dysbiosis. We report that visceral adipose and intestinal tissues are highly vulnerable to cellular senescence due to an increase in DNA damage response, activation of cell cycle inhibitors, and senescence-associated secretory phenotype regulators. With advancing age, dysregulation in nutrient signaling mediators (AMPK/AKT/SIRT3/5), and a decrease in autophagy was also observed. Inflamm-aging markers (TNF-α/IL-1β) and splenic CD4/CD8 T cell ratio increased with age, while NK cell population decreased. Metagenomic analyses revealed an age-related decrease in the diversity of microbial species and an increase in the abundance of various pathogenic bacterial species. On the other hand, long-term EGCG consumption significantly attenuated markers of DNA damage, cell cycle inhibitors, senescence-associated secretory phenotype regulators, AMPK/AKT signaling, and enhanced SIRT3/5 expression and autophagy. Systemic inflamm-aging indicators decreased, while early T cell activation increased in EGCG fed animals. EGCG also suppressed the abundance of pathogenic bacteria and preserved microbial diversity. Our results suggest that adipose and intestine tissues are prone to cellular senescence and that chronic consumption of EGCG can attenuate several deleterious aspects of aging which could be implicated in developing anti-aging strategies.