Padwad, Y. | bioRxiv Science

bioRxiv2021

Long term consumption of green tea EGCG enhances healthspan and lifespan in mice bymitigating multiple aspects of cellular senescence in mitotic and post-mitotic tissues, gutdysbiosis and immunosenescence

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-{kappa}B/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-/IL-l{beta}) 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.

molecular biology↗

bioRxiv2020

Various RNA-binding proteins and their conditional networks explain miRNA biogenesis and help to reveal the potential SARS-CoV-2 host miRNAome system

Formation of mature miRNAs and their expression is a highly controlled process. It is very much dependent upon the post-transcriptional regulatory events. Recent findings suggest that several RNA binding proteins beyond Drosha/Dicer are involved in the processing of miRNAs. Deciphering of conditional networks for these RBP-miRNA interactions may help to reason the spatio-temporal nature of miRNAs which can also be used to predict miRNA profiles. In this direction, >25TB of data from different platforms were studied (CLIP-seq/RNA-seq/miRNA-seq) to develop Bayesian causal networks capable of reasoning miRNA biogenesis. The networks ably explained the miRNA formation when tested across a large number of conditions and experimentally validated data. The networks were modeled into an XGBoost machine learning system where expression information of the network components was found capable to quantitatively explain the miRNAs formation levels and their profiles. The models were developed for 1,204 human miRNAs whose accurate expression level could be detected directly from the RNA-seq data alone without any need of doing separate miRNA profiling experiments like miRNA-seq or arrays. A first of its kind, miRbiom performed consistently well with high average accuracy (91%) when tested across a large number of experimentally established data from several conditions. It has been implemented as an interactive open access web-server where besides finding the profiles of miRNAs, their downstream functional analysis can also be done. miRbiom will help to get an accurate prediction of human miRNAs profiles in the absence of profiling experiments and will be an asset for regulatory research areas. The study also shows the importance of having RBP interaction information in better understanding the miRNAs and their functional projectiles where it also lays the foundation of such studies and software in future.

bioinformatics↗