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Published on: June 28, 2019
Exploring the uncharted role of cell senescence in rare diseases
Piera Selvaggio1, Esi Taci1,2, Alessandra Barassi1,3
1Department of Health Sciences, University of Milan, Via Antonio di Rudinì 8, Milano, Italy.
Background:
Cellular senescence is a biological process in which the cell cycle is arrested in response to DNA damage caused by different endogenous and exogenous stimuli. In senescent cells, activation of intracellular cascade induces epigenetic, morphological and metabolic changes. Among them, senescent status is characterized by an alteration of the epigenome and the establishment of a peculiar senescence-associated secretory phenotype (SASP), which contributes to the extracellular matrix remodeling and senescence spreading. Growing interest is directed towards senescence relevance both in physiological processes and in pathological ones, including rare progeroid syndromes. However, little is known about senescence contribution to the onset and development of rare diseases in which aging traits are not manifested.
Main Body:
Here, we review the current knowledge about senescence involvement in four rare mendelian disorders of the epigenetic machinery (i.e. chromatinopathies) and four rare lung diseases, that can be considered a paradigm for understanding how epigenome alteration and aberrant microenvironment modification in senescence process might drive disease onset and progression. First, we report the main characteristics of chromatinopathies and the relation between the chromatin-related epigenetic defects and the senescence features in Sotos syndrome, Cornelia de Lange syndrome, Rett syndrome, and Kleefstra syndromes. Thereafter, we describe the pathological alteration and senescence involvement in cystic fibrosis, idiopathic pulmonary fibrosis, pulmonary arterial hypertension and lymphangioleiomyomatosis, considering them as models of rare lung diseases in which accumulation of senescent cells and their proinflammatory SASP have a central role.
Conclusion:
Exploring the role of senescence in different and less common diseases might promote the understanding of the senescent process as a novel player in rare disorders, for a more comprehensive vision of their complexity and the suggestion of novel possible therapeutical targets.
Insights
Cellular senescence, a process involving cell cycle arrest and epigenetic changes, is increasingly linked to rare diseases. This review explores its role in chromatinopathies and lung diseases, suggesting new therapeutic targets.
Area of Science:
- Cellular and Molecular Biology
- Genetics and Epigenetics
- Rare Diseases Research
Background:
- Cellular senescence involves cell cycle arrest, epigenetic alterations, and a senescence-associated secretory phenotype (SASP).
- Senescence is implicated in physiological and pathological processes, including rare progeroid syndromes.
- Its role in rare diseases without overt aging traits remains largely unknown.
Purpose of the Study:
- To review the involvement of cellular senescence in rare mendelian disorders of the epigenetic machinery (chromatinopathies) and rare lung diseases.
- To understand how epigenome alterations and microenvironment modifications in senescence drive disease onset and progression.
- To explore senescence as a potential factor in rare diseases lacking typical aging features.
Main Methods:
- Review of current knowledge on senescence in four chromatinopathies: Sotos, Cornelia de Lange, Rett, and Kleefstra syndromes.
- Analysis of senescence involvement in four rare lung diseases: cystic fibrosis, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, and lymphangioleiomyomatosis.
- Examination of the relationship between epigenetic defects, SASP, and disease progression in selected rare disorders.
Main Results:
- Chromatinopathies exhibit epigenetic defects linked to senescence features.
- Rare lung diseases show accumulation of senescent cells and a proinflammatory SASP playing a central role.
- Senescence contributes to disease onset and progression through epigenome alteration and microenvironment modification.
Conclusions:
- Investigating senescence in diverse rare diseases enhances understanding of its role in complex disorders.
- Senescence emerges as a novel player in the pathogenesis of rare conditions.
- This research may lead to novel therapeutic targets for rare diseases.
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