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Published on: April 10, 2018
Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and
Xinghui Sun1,2,3, Mark W Feinberg4
1Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, United States.
Abstract:
Cellular senescence is a stable form of cell cycle arrest in response to various stressors. While it serves as an endogenous pro-resolving mechanism, detrimental effects ensue when it is dysregulated. In this review, we introduce recent advances for cellular senescence and inflammaging, the underlying mechanisms for the reduction of nicotinamide adenine dinucleotide in tissues during aging, new knowledge learned from p16 reporter mice, and the development of machine learning algorithms in cellular senescence. We focus on pathobiological insights underlying cellular senescence of the vascular endothelium, a critical interface between blood and all tissues. Common causes and hallmarks of endothelial senescence are highlighted as well as recent advances in endothelial senescence. The regulation of cellular senescence involves multiple mechanistic layers involving chromatin, DNA, RNA, and protein levels. New targets are discussed including the roles of long noncoding RNAs in regulating endothelial cellular senescence. Emerging small molecules are highlighted that have anti-aging or anti-senescence effects in age-related diseases and impact homeostatic control of the vascular endothelium. Lastly, challenges and future directions are discussed including heterogeneity of endothelial cells and endothelial senescence, senescent markers and detection of senescent endothelial cells, evolutionary differences for immune surveillance in mice and humans, and long noncoding RNAs as therapeutic targets in attenuating cellular senescence. Accumulating studies indicate that cellular senescence is reversible. A better understanding of endothelial cellular senescence through lifestyle and pharmacological interventions holds promise to foster a new frontier in the management of cardiovascular disease risk.
Insights
Cellular senescence, a state of irreversible cell cycle arrest, contributes to aging and disease when dysregulated. Reversing endothelial senescence offers a promising strategy for managing cardiovascular disease risk.
Area of Science:
- Gerontology and Cellular Biology
- Cardiovascular Research
- Molecular Medicine
Background:
- Cellular senescence is a protective cell cycle arrest mechanism that can become detrimental when dysregulated, contributing to aging and age-related diseases.
- Endothelial cells, crucial for vascular health, are susceptible to senescence, impacting tissue homeostasis and cardiovascular function.
- Inflammaging, a chronic low-grade inflammation associated with aging, is linked to cellular senescence and reduced NAD+ levels.
Purpose of the Study:
- To review recent advances in understanding cellular senescence, focusing on endothelial senescence and its role in vascular health.
- To explore the mechanisms underlying cellular senescence, including NAD+ reduction, p16 reporter mouse studies, and machine learning applications.
- To highlight novel therapeutic targets and interventions for attenuating cellular senescence and mitigating age-related cardiovascular risks.
Main Methods:
- Review of current literature on cellular senescence, inflammaging, and endothelial cell biology.
- Analysis of molecular mechanisms regulating senescence at chromatin, DNA, RNA, and protein levels.
- Discussion of emerging therapeutic strategies, including small molecules and long noncoding RNAs.
Main Results:
- Endothelial senescence is driven by various stressors, characterized by specific hallmarks, and influenced by factors like NAD+ metabolism.
- Long noncoding RNAs (lncRNAs) play a significant role in regulating endothelial senescence.
- Emerging small molecules and interventions show potential in reversing senescence and improving vascular homeostasis.
Conclusions:
- Cellular senescence, particularly in the vascular endothelium, is a key contributor to aging and cardiovascular disease.
- Understanding the heterogeneity and detection of senescent cells is crucial for developing effective therapies.
- Targeting endothelial senescence through lifestyle or pharmacological interventions represents a promising frontier for cardiovascular disease management.
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