Research Article: Molecular links between cellular senescence, longevity and age-related diseases – a systems biology perspective

Date Published: December 18, 2011

Publisher: Impact Journals LLC

Author(s): Robi Tacutu, Arie Budovsky, Hagai Yanai, Vadim E. Fraifeld.

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Abstract

The role of cellular senescence (CS) in age-related diseases (ARDs) is a quickly emerging topic in aging research. Our comprehensive data mining revealed over 250 genes tightly associated with CS. Using systems biology tools, we found that CS is closely interconnected with aging, longevity and ARDs, either by sharing common genes and regulators or by protein-protein interactions and eventually by common signaling pathways. The most enriched pathways across CS, ARDs and aging-associated conditions (oxidative stress and chronic inflammation) are growth-promoting pathways and the pathways responsible for cell-extracellular matrix interactions and stress response. Of note, the patterns of evolutionary conservation of CS and cancer genes showed a high degree of similarity, suggesting the co-evolution of these two phenomena. Moreover, cancer genes and microRNAs seem to stand at the crossroad between CS and ARDs. Our analysis also provides the basis for new predictions: the genes common to both cancer and other ARD(s) are highly likely candidates to be involved in CS and vice versa. Altogether, this study shows that there are multiple links between CS, aging, longevity and ARDs, suggesting a common molecular basis for all these conditions. Modulating CS may represent a potential pro-longevity and anti-ARDs therapeutic strategy.

Partial Text

Since Hayflick’s discovery of the phenomenon of cellular (replicative) senescence [1], the contribution or even relevance of this phenomenon to organismal aging has been a subject for continuous debates [2-5]. Although the question still remains open, an increasing amount of evidence, especially from recent years, indicates that cellular senescence (CS) could have a role in aging and age-related diseases (ARDs), rather than being just a laboratory phenomenon [3, 6-11]. In fact, the current situation in the field could be defined as an attempt to understand to what extent and how is CS involved in aging and ARDs.

Our study shows that CS is tightly interconnected to aging, longevity and ARDs, either by sharing common genes and regulators or by PPIs and eventually by common pathways. The identification of a common molecular basis is an important step towards understanding the relationships between all these conditions. The next natural step would be the integration of these data with gene/miRNA expression profiles. Such integration could further highlight the key players in linking CS and ARDs. However, this is not a trivial task as the vast majority of data concerning CS derives from in vitro studies on fibroblasts while ARDs are well studied in a variety of cells and in vivo systems. Broadening the CS investigation by including more cell types, 3D in vitro models and in vivo studies will help in developing a more holistic view on the CS phenomenon.

A list of genes that have been established as being involved in CS was compiled from scientific literature and manually curated. The selection of genes was based on two lines of evidence: 1) genetic or RNA interference (RNAi) interventions (gene knockout, partial or full loss-of-function mutations, RNAi-induced gene silencing, overexpression) which reportedly cause cells to either induce, inhibit or reverse CS, and 2) genes shown to be markers of CS. The lists of LAGs and the genes involved in ARDs and aging-associated processes (oxidative stress and chronic inflammation) were obtained from databases and scientific literature as described in detail elsewhere [23, 24, 81]. The list of differentially expressed miRNAs in CS and of those which have been shown to affect CS was gathered and manually curated from the scientific literature [82-86]. Annotations regarding the involvement of miRNAs in different ARDs were taken from the Human MicroRNA Disease Database ([87], http://cmbi.bjmu.cn/hmdd). Oncogene/Tumor Suppressor classification of cancer-associated miRNAs was done according to Wang et al. [38]. Experimentally validated targets of miRNAs have been obtained from the TarBase database ([88], http://diana.cslab.ece.ntua.gr/tarbase/) and updated by data mining from the scientific literature.

 

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