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-1β) 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.

中文翻译：

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长期食用绿茶EGCG可减轻有丝分裂和有丝分裂后组织的细胞衰老，肠道营养不良和免疫衰老的多个方面，从而提高小鼠的健康水平和寿命。

细胞衰老正逐渐成为衰老的因果关系，其潜在的调节剂提出了一种有效的策略来对抗与年龄相关的发病率。当前的研究概述了在寿命的四个不同时间点小鼠不同器官中细胞衰老的程度，并探讨了表没食子儿茶素没食子酸酯（EGCG）的消耗对衰老生物学的多个方面的影响。我们报告说，脂肪和肠道组织高度易受细胞衰老的影响，这与年龄相关的DNA损伤反应增加，细胞周期抑制剂（p53 / p21）激活和SASP诱导（p38MAPK /NF-κB/ Cox-2）明显相关。此外，在衰老的动物中也观察到营养信号传导途径介体（AMPK / Akt / SIRT3和5）的独特调节，以及自噬效应子的减少。随着年龄的增长，全身性炎症老化标记物（TNF-α/IL-1β）和脾脏CD4 / CD8比值增加，而NK细胞数量减少。元基因组学分析显示，与年龄相关的微生物物种多样性下降，同时还观察到各种病原细菌属的丰度增加。长期食用EGCG可以减轻脂肪，肠和肝组织中的DNA损伤标记，细胞周期抑制剂和SASP，从而延长动物的寿命。从机理上讲，EGCG抑制AMPK和Akt的活化并增强线粒体SIRT3和SIRT5的表达，以及在脂肪和肠组织中的自噬反应。在饲喂EGCG的动物中，炎症衰老标记的系统性存在减少，而T细胞免疫应答调节剂CD69的表达增加。EGCG还改善了与年龄相关的微生物物种多样性下降，并抑制了病原微生物的生长。简而言之，我们的结果提供了令人信服的证据，即有丝分裂后的脂肪组织是细胞衰老和SASP活化的主要部位，并且长期食用EGCG可以影响衰老和衰老的多个方面，从而改善了机体的健康状况和寿命。