Epigenetic Basis of Cellular Senescence and Its Implications in Aging

Nacarelli, Timothy; Liu, Pingyu; Zhang, Rugang

doi:10.3390/genes8120343

Cited by 49 publications

(32 citation statements)

References 85 publications

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“…DNA methylation has been recognized as a critical mechanism promoting senescence and ageing at the molecular and cellular levels [149][150][151][152][153]. The DNA methylome of senescent cells shows extensive hypomethylation and formation of facultative heterochromatin domains compared to proliferating normal cells.…”

Section: Epigenetics Of Ageing: a Focus On Dna Methylationmentioning

confidence: 99%

“…There is extensive evidence of the importance of DNA hypomethylation as a senescence inducer. First, this occurs in pre-senescent cells, but not in immortalized cells where the overall methylation level is relatively stable, indicating that DNA methylation dynamics are related to a limited proliferative lifetime [150,153]. It was, therefore, postulated that DNA hypomethylation may function as a mitotic clock, similar to TL shortening [148].…”

Section: Epigenetics Of Ageing: a Focus On Dna Methylationmentioning

confidence: 99%

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Molecular basis of ageing in chronic metabolic diseases

Spinelli

Parrillo

Longo

et al. 2020

J Endocrinol Invest

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Aim Over the last decades, the shift in age distribution towards older ages and the progressive ageing which has occurred in most populations have been paralleled by a global epidemic of obesity and its related metabolic disorders, primarily, type 2 diabetes (T2D). Dysfunction of the adipose tissue (AT) is widely recognized as a significant hallmark of the ageing process that, in turn, results in systemic metabolic alterations. These include insulin resistance, accumulation of ectopic lipids and chronic inflammation, which are responsible for an elevated risk of obesity and T2D onset associated to ageing. On the other hand, obesity and T2D, the paradigms of AT dysfunction, share many physiological characteristics with the ageing process, such as an increased burden of senescent cells and epigenetic alterations. Thus, these chronic metabolic disorders may represent a state of accelerated ageing. Materials and methods A more precise explanation of the fundamental ageing mechanisms that occur in AT and a deeper understanding of their role in the interplay between accelerated ageing and AT dysfunction can be a fundamental leap towards novel therapies that address the causes, not just the symptoms, of obesity and T2D, utilizing strategies that target either senescent cells or DNA methylation. Results In this review, we summarize the current knowledge of the pathways that lead to AT dysfunction in the chronological ageing process as well as the pathophysiology of obesity and T2D, emphasizing the critical role of cellular senescence and DNA methylation. Conclusion Finally, we highlight the need for further research focused on targeting these mechanisms.

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Section: Epigenetics Of Ageing: a Focus On Dna Methylationmentioning

confidence: 99%

Section: Epigenetics Of Ageing: a Focus On Dna Methylationmentioning

confidence: 99%

Molecular basis of ageing in chronic metabolic diseases

Spinelli

Parrillo

Longo

et al. 2020

J Endocrinol Invest

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“…Cellular senescence refers to the irreversible arrest of cell proliferation in response to various stresses. Senescent cells secrete cytokines that can promote clearance of the tumor by the immune system; therefore, inducing senescence may be an avenue for cancer treatment [74]. Another hallmark of senescent cells is an increase in facultative heterochromatin known as senescence-associated heterochromatin foci (SAHF), a process which involves focal deposition of macro2HA and HP1 family proteins as well as H3K9 tri-methylation.…”

Section: Biology Of Atrxmentioning

confidence: 99%

Mutant ATRX: uncovering a new therapeutic target for glioma

Haase

Garcia-Fabiani

Carney

et al. 2018

Expert Opinion on Therapeutic Targets

115

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Introduction ATRX is a chromatin remodeling protein whose main function is the deposition of the histone variant H3.3. ATRX mutations are widely distributed in glioma, and correlate with alternative lengthening of telomeres (ALT) development, but they also affect other cellular functions related to epigenetic regulation. Areas covered We discuss the main molecular characteristics of ATRX, from its various functions in normal development to the effects of its loss in ATRX syndrome patients and animal models. We focus on the salient consequences of ATRX mutations in cancer, from a clinical to a molecular point of view, focusing on both adult and pediatric glioma. Finally, we will discuss the therapeutic opportunities future research perspectives. Expert opinion ATRX is a major component of various essential cellular pathways, exceeding its functions as a histone chaperone (e.g., DNA replication and repair, chromatin higher-order structure regulation, gene transcriptional regulation, etc.). However, it is unclear how the loss of these functions in ATRX-null cancer cells affects cancer development and progression. We anticipate new treatments and clinical approaches will emerge for glioma and other cancer types as mechanistic and molecular studies on ATRX are only just beginning to reveal the many critical functions of this protein in cancer.

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“…An independent upregulation of CDKN2A/p16INK4A, an inhibitor of cyclin dependent kinases 4 and 6, cooperates with p21 to reduce the phosphorylation of retinoblastoma (Rb) protein and arrest cells at the G1 phase [4,12]. These upstream signals also maintain the active metabolic state of senescent cells while promoting marked changes in the gene expression program such as downregulation of cell cycle genes and upregulation of SASP genes [13,14].…”

Section: Cellular Senescence and Senotherapiesmentioning

confidence: 99%

The senescent cell epigenome

Yang

Sen

2018

Aging

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A critical hallmark of aging is cellular senescence, a state of growth arrest and inflammatory cytokine release in cells, caused by a variety of stresses. Recent work has convincingly linked the accumulation of senescent cells in aged tissues to a decline in health and a limit of lifespan, primarily through "inflammaging". Importantly, interventions that clear senescent cells have achieved marked improvements in healthspan and lifespan in mice. A growing list of studies show that environmental stimuli can affect aging and longevity through conserved pathways which, in turn, modulate chromatin states. This review consolidates key findings of chromatin state changes in senescence including histone modifications, histone variants, DNA methylation and changes in three-dimensional genome organization. This information will facilitate the identification of mechanisms and discovery of potential epigenetic targets for therapeutic interventions in aging and age-related disease.

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Epigenetic Basis of Cellular Senescence and Its Implications in Aging

Cited by 49 publications

References 85 publications

Molecular basis of ageing in chronic metabolic diseases

Molecular basis of ageing in chronic metabolic diseases

Mutant ATRX: uncovering a new therapeutic target for glioma

The senescent cell epigenome

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