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

Abstract

Cellular senescence is emerging as the causal nexus of aging, and its potential modulators present an effective strategy to counter age-related morbidity. The current study profiled the extent of cellular senescence in different organs of mice at four different time-points of lifespan, and explored the influence of epigallocatechin gallate (EGCG) consumption in impacting multiple aspects of aging biology. We report that adipose and intestinal tissues are highly vulnerable to cellular senescence as evident by age-associated increase in DNA damage response, activation of cell cycle inhibitors (p53/p21) and induction of SASP (p38MAPK/NF-κB/Cox-2). Further, a distinct modulation of nutrient signaling pathway mediators (AMPK/Akt/SIRT3 and 5), and a decrease in autophagy effectors was also observed in aging animals. Systemic inflamm-aging markers (TNF-α/IL-lβ) and splenic CD4/CD8 ratio increased with age, while NK cell population decreased. Metagenomic analyses revealed age-related decrease in the diversity of microbial species while an increase in the abundance of various pathogenic bacterial genera was also observed. Long term EGCG consumption enhanced lifespan of animals by attenuating markers of DNA damage, cell cycle inhibitors and SASP in adipose, intestine and liver tissue. Mechanistically, EGCG inhibited the activation of AMPK and Akt and enhanced mitochondrial SIRT3 and SIRT5 expression, as well as autophagic response in adipose and intestinal tissues. Systemic presence of inflamm-aging markers decreased while expression of T cell immune response regulator CD69 increased in EGCG fed animals. EGCG also improved age-related decrease in the diversity of microbial species and suppressed the growth of pathogenic microbes. In short, our results provide compelling evidence that post-mitotic adipose tissue is a major site of cellular senescence and SASP activation, and that chronic EGCG consumption can influence several aspects of aging and senescence resulting in improved organismal healthspan and lifespan.

Iron: an underrated factor in aging

“…EGCG extends the lifespan and healthspan of mice, attenuating markers of DNA damage and senescence-associated secretory profile, and increasing activation of autophagy [ 23 ]. EGCG also extends the lifespan of rats by reducing liver and kidney damage and inhibiting inflammation and oxidative stress [ 24 ].…”

Emerging Interrelationship Between the Gut Microbiome and Cellular Senescence in the Context of Aging and Disease: Perspectives and Therapeutic Opportunities

“…Similarly, another report revealed that intestinal tissue developed strong signatures of cellular senescence as evident by increased expression of senescence markers—p16 Ink4a , p21 Cip1 , and SA-β-gal activity in both WT mice and accelerated aging mice model— Ercc1 −/Δ [ 148 ]. We also observed an age-dependent increase in DNA damage, cellular senescence (p53/p21 WAF1 ), activation of SASP regulators (NFκB, p38MAPK, Cox-2), and metabolic stress in the intestinal tissue of aged mice indicating their vulnerability to spontaneous age-related genotoxic stress [ 149 ]. In addition, intestinal epithelial organoids derived from aged mice also showed consistent upregulation of senescence markers such as SA-β-gal activity and p21 as compared to organoids derived from younger organisms [ 150 ].…”

“…It is thus evident that intestinal epithelial, as well as stem cells, exhibit age-dependent cellular senescence which can contribute to known functional alterations and disruption of gastrointestinal homeostasis. Moreover, the chronic SASP secreted by senescent intestinal cells can promote inflammatory environment and/or oncogenic transformation which can have harmful effects on gut permeability, immune activation as well as gut microbiome composition [ 149 , 152 ] (Fig. 3 ).…”

“…Remarkably, specific microbial populations in ileal, cecal, colonic, and fecal regions were also distinctly modulated by D + Q, suggesting that senolytics might improve health via reducing intestinal senescence, inflammation, and gut microbial dysbiosis in older subjects [ 163 ]. Our recent report also observed that dietary consumption of another putative senolytic, green tea EGCG, decreased SC burden in multiple tissues which correlated with increased suppression of pathogenic bacteria in the gut microbiome of aged mice [ 149 ]. Another natural senolytic fistein, which is abundant in numerous fruits and vegetables, can suppress premature ovarian failure [ 165 ] and age-related Parkinson’s disease by regulating the composition of gut microbiota [ 166 ].…”

Structured Long-Chain Omega-3 Fatty Acids for Improvement of Cognitive Function during Aging

“…Increased oxidative stress can directly accelerate the development of cellular stress and establish a senescence program in different cells. Nutritional status can be of particular importance in this context as several studies have shown that consumption of antioxidant compounds like the green tea component epigallocatechin gallate (EGCG) [ 19 ], resveratrol [ 20 ], quercetin [ 21 ], vitamin C [ 22 ], and minerals such as zinc [ 23 ], have proven anti-cellular senescence attributes through improved redox homeostasis in both in vitro and in vivo studies [ 24 ].…”