Dataset Information

Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies.

ABSTRACT: Life expectancy has drastically increased over the last few decades worldwide, with important social and medical burdens and costs. To stay healthy longer and to avoid chronic disease have become essential issues. Organismal aging is a complex process that involves progressive destruction of tissue functionality and loss of regenerative capacity. One of the most important aging hallmarks is cellular senescence, which is a stable state of cell cycle arrest that occurs in response to cumulated cell stresses and damages. Cellular senescence is a physiological mechanism that has both beneficial and detrimental consequences. Senescence limits tumorigenesis, lifelong tissue damage, and is involved in different biological processes, such as morphogenesis, regeneration, and wound healing. However, in the elderly, senescent cells increasingly accumulate in several organs and secrete a combination of senescence associated factors, contributing to the development of various age-related diseases, including cancer. Several studies have revealed major molecular pathways controlling the senescent phenotype, as well as the ones regulating its interactions with the immune system. Attenuating the senescence-associated secretory phenotype (SASP) or eliminating senescent cells have emerged as attractive strategies aiming to reverse or delay the onset of aging diseases. Here, we review current senotherapies designed to suppress the deleterious effect of SASP by senomorphics or to selectively kill senescent cells by "senolytics" or by immune system-based approaches. These recent investigations are promising as radical new controls of aging pathologies and associated multimorbidities.

SUBMITTER: Khalil R

PROVIDER: S-EPMC10047596 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies.

Khalil Roula R Diab-Assaf Mona M Lemaitre Jean-Marc JM

Cells 20230316 6

Life expectancy has drastically increased over the last few decades worldwide, with important social and medical burdens and costs. To stay healthy longer and to avoid chronic disease have become essential issues. Organismal aging is a complex process that involves progressive destruction of tissue functionality and loss of regenerative capacity. One of the most important aging hallmarks is cellular senescence, which is a stable state of cell cycle arrest that occurs in response to cumulated cel ...[more]

PMID: 36980256

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Project description:In toxicogenomics, functional annotation is an important step to gain additional insights into genes with aberrant expression that drive pathophysiological mechanisms. Nevertheless, there exists a gap on annotation of these genes which often hampers the interpretation of results and limits their applicability in translational medicine. In this study, we evaluated the coverage of functional annotations of differentially expressed genes (DEGs) induced by 10 selected compounds from the TG-GATEs database identified as high- or no-risk in causing drug-induced liver injury (most-DILI or no-DILI, respectively) using in vitro human data. Functional roles of DEGs not present in the most common biological annotation databases - termed "dark genes" - were unveiled via literature mining and via the identification of shared regulatory transcription factors or signaling pathways. Our results demonstrated that there were approximately 13% of dark genes induced by these compounds in vitro and we were able to obtain additional relevant information for up to 76% of those. Using interactome data from several sources, we have uncovered genes such as LRBA, and WDR26 as highly connected in the protein network that play roles in drug response. Genes such as MALAT1, H19, and MIR29C - whose links to hepatotoxicity have been confirmed - were identified as markers for the most-DILI group and appeared as top hits across all literature-based mining methods. Furthermore, we investigated the potential impact of dark genes on liver toxicity by identifying their rat orthologs in combination with their correlation to drug-induced liver pathologies observed in vivo following chemical exposure. We identified a set of important regulatory transcription factors of dark genes for all most-DILI compounds including E2F1 and JUND with supporting evidences in literature and we found Magee1 correlated with chemically induced bile duct hyperplasia and adverse responses at 29 days in rats in vivo. In conclusion, in this study we show the potential role of these poorly annotated genes in mechanisms underlying hepatotoxicity and offer a number of computational approaches that may help to minimize current gaps in gene annotation and highlight their values as potential biomarkers in toxicological studies.

Dataset Information

Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies.

Publications

Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies.

Similar Datasets

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