Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition

Crespo-Garcia, Sergio; Tsuruda, Pamela R.; Dejda, Agnieszka; Ryan, Rathi D.; Fournier, Frédérik; Chaney, S.; Pilon, Frédérique; Dogan, Taner; Cagnone, Gaël; Patel, Parimal; Buscarlet, Manuel; Dasgupta, Sonali; Girouard, Gabrielle; Rao, Surabhi R.; Wilson, Ariel M.; O’Brien, Robert; Juneau, Rachel; Guber, Vera; Dubrac, Alexandre; Beauséjour, Christian; Armstrong, Scott A.; Mallette, Frédérick A.; Yohn, Christopher B.; Joyal, Jean‐Sébastien; Marquess, Dan; Beltran, Pedro J.; Sapieha, Przemysław

doi:10.1016/j.cmet.2021.01.011

Cited by 108 publications

(77 citation statements)

References 81 publications

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“…Similarly, peripheral senescence can result in insulin resistance 169 , while insulin resistance in turn drives stress and senescence in pancreatic β-cells 171 . This degenerative cycle leads to elevated blood glucose and senescence in the eye and kidney, ultimately driving diabetic complications 172,174 (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, insulin resistance can drive hyperinsulinemia and promote β-cell senescence 171 , implicating peripheral senescent cells as feedback drivers of senescence in the pancreas. Furthermore, complications of diabetes, including diabetic kidney disease 172,173 and diabetic retinopathy 174 , potentially result from senescent cells driven by increased blood glucose levels, as described above. In each case, senolytic therapies improve health outcomes in terms of either blood glucose levels 168,169,171 or development of diabetes-driven complications 172,174 .…”

Section: Interventions That Reciprocally Target Senescence and Metabolismmentioning

confidence: 99%

“…Furthermore, complications of diabetes, including diabetic kidney disease 172,173 and diabetic retinopathy 174 , potentially result from senescent cells driven by increased blood glucose levels, as described above. In each case, senolytic therapies improve health outcomes in terms of either blood glucose levels 168,169,171 or development of diabetes-driven complications 172,174 . Together, these studies implicate senescent cells as a major nexus for interventions into diabetes and its associated disorders.…”

Section: Interventions That Reciprocally Target Senescence and Metabolismmentioning

confidence: 99%

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The metabolic roots of senescence: mechanisms and opportunities for intervention

2021

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Cellular senescence entails a permanent proliferative arrest, coupled to multiple phenotypic changes. Among these changes is the release of numerous biologically active molecules collectively known as the senescence-associated secretory phenotype, or SASP. A growing body of literature indicates that both senescence and the SASP are sensitive to cellular and organismal metabolic states, which in turn can drive phenotypes associated with metabolic dysfunction. Here, we review the current literature linking senescence and metabolism, with an eye toward findings at the cellular level, including both metabolic inducers of senescence and alterations in cellular metabolism associated with senescence. Additionally, we consider how interventions that target either metabolism or senescent cells might influence each other and mitigate some of the pro-aging effects of cellular senescence. We conclude that the most effective interventions will likely break a degenerative feedback cycle by which cellular senescence promotes metabolic diseases, which in turn promote senescence.

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Section: Discussionmentioning

confidence: 99%

Section: Interventions That Reciprocally Target Senescence and Metabolismmentioning

confidence: 99%

Section: Interventions That Reciprocally Target Senescence and Metabolismmentioning

confidence: 99%

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The metabolic roots of senescence: mechanisms and opportunities for intervention

2021

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“…Angiogenesis can improve myocardial cell survival and preserve heart function following acute MI. Studies have shown that SASP-related inflammatory cytokines can promote the formation of new capillaries by sprouting preexisting vessels [ 97 ]. Of note, genetic inactivation of senescence by ATM haplodeficiency inhibited angiogenesis and endothelial tubing formation in response to acute MI, which accelerated heart failure in vivo [ 80 ].…”

Section: Consequence Of Cellular Senescence In Cardiovascular Diseasesmentioning

confidence: 99%

Cellular Senescence in Cardiovascular Diseases: A Systematic Review

Hu¹,

Zhang²,

Teng³

et al. 2022

Aging and disease

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Aging is a prominent risk factor for cardiovascular diseases, which is the leading cause of death around the world. Recently, cellular senescence has received potential attention as a promising target in preventing cardiovascular diseases, including acute myocardial infarction, atherosclerosis, cardiac aging, pressure overload-induced hypertrophy, heart regeneration, hypertension, and abdominal aortic aneurysm. Here, we discuss the mechanisms underlying cellular senescence and describe the involvement of senescent cardiovascular cells (including cardiomyocytes, endothelial cells, vascular smooth muscle cells, fibroblasts/myofibroblasts and T cells) in age-related cardiovascular diseases. Then, we highlight the targets (SIRT1 and mTOR) that regulating cellular senescence in cardiovascular disorders. Furthermore, we review the evidence that senescent cells can exert both beneficial and detrimental implications in cardiovascular diseases on a context-dependent manner. Finally, we summarize the emerging pro-senescent or anti-senescent interventions and discuss their therapeutic potential in preventing cardiovascular diseases.

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“…The role of senescent ECs was examined recently in diabetic retinopathy ( Crespo-Garcia et al, 2021 ). Senescent ECs accumulate in retinas during peak pathological neovascularization in a mouse model of ischemic retinopathy and of patients with diabetic retinopathy.…”

Section: Cellular Senescence Of Endothelial Cellsmentioning

confidence: 99%

Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and Therapeutic Opportunities

Sun

Feinberg

2021

Front. Physiol.

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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.

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Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition

Cited by 108 publications

References 81 publications

The metabolic roots of senescence: mechanisms and opportunities for intervention

The metabolic roots of senescence: mechanisms and opportunities for intervention

Cellular Senescence in Cardiovascular Diseases: A Systematic Review

Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and Therapeutic Opportunities

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