Senescence in Health and Disease

He, Shirley; Sharpless, Norman E.

doi:10.1016/j.cell.2017.05.015

Cited by 1,162 publications

(992 citation statements)

References 105 publications

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“…Emphysema accompanies cellular senescence, and the incidence of this disease increases with age (Karrasch, Holz, & Jörres, 2008; Tsuji et al, 2006). Recent studies on the genetic and pharmacological ablation of senescent cells have demonstrated that these cells underlie several diseases (He & Sharpless, 2017). Our results also suggest that the elimination of p19 ARF ‐expressing cells in ARF‐DTR mice protects lung tissues against PPE‐induced emphysema.…”

Section: Discussionmentioning

confidence: 99%

Elimination of p19^ARF‐expressing cells protects against pulmonary emphysema in mice

et al. 2018

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Senescent cells accumulate in tissues during aging and are considered to underlie several aging‐associated phenotypes and diseases. We recently reported that the elimination of p19ARF‐expressing senescent cells from lung tissue restored tissue function and gene expression in middle‐aged (12‐month‐old) mice. The aging of lung tissue increases the risk of pulmonary diseases such as emphysema, and cellular senescence is accelerated in emphysema patients. However, there is currently no direct evidence to show that cellular senescence promotes the pathology of emphysema, and the involvement of senescence in the development of this disease has yet to be clarified. We herein demonstrated that p19ARF facilitated the development of pulmonary emphysema in mice. The elimination of p19ARF‐expressing cells prevented lung tissue from elastase‐induced lung dysfunction. These effects appeared to depend on reduced pulmonary inflammation, which is enhanced after elastase stimulation. Furthermore, the administration of a senolytic drug that selectively kills senescent cells attenuated emphysema‐associated pathologies. These results strongly suggest the potential of senescent cells as therapeutic/preventive targets for pulmonary emphysema.

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Section: Discussionmentioning

confidence: 99%

Elimination of p19^ARF‐expressing cells protects against pulmonary emphysema in mice

et al. 2018

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“…Cellular senescence plays an instrumental role in limiting the development of pathological states including cancer, but the accumulation of senescent cells with aging also contributes to age‐related tissue dysfunction (He & Sharpless, 2017). Cellular senescence is a complex phenotype characterized by two arms: a stress‐induced, durable cell cycle arrest and the production of a suite of pro‐inflammatory molecules known as the senescence‐associated secretory phenotype (SASP) (Childs, Durik, Baker & van Deursen, 2015; Coppe, Desprez, Krtolica & Campisi, 2010; Munoz‐Espin & Serrano, 2014).…”

Section: Introductionmentioning

confidence: 99%

Expression of p16^INK^4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

et al. 2018

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SummaryCellular senescence drives a functional decline of numerous tissues with aging by limiting regenerative proliferation and/or by producing pro‐inflammatory molecules known as the senescence‐associated secretory phenotype (SASP). The senescence biomarker p16 INK 4a is a potent inhibitor of the cell cycle but is not essential for SASP production. Thus, it is unclear whether p16 INK 4a identifies senescence in hyporeplicative cells such as articular chondrocytes and whether p16 INK 4a contributes to pathologic characteristics of cartilage aging. To address these questions, we examined the role of p16 INK 4a in murine and human models of chondrocyte aging. We observed that p16 INK 4a mRNA expression was significantly upregulated with chronological aging in murine cartilage (~50‐fold from 4 to 18 months of age) and in primary human chondrocytes from 57 cadaveric donors (r 2 = .27, p < .0001). Human chondrocytes exhibited substantial replicative potential in vitro that depended on the activity of cyclin‐dependent kinases 4 or 6 (CDK4/6), and proliferation was reduced in cells from older donors with increased p16 INK 4a expression. Moreover, increased chondrocyte p16 INK 4a expression correlated with several SASP transcripts. Despite the relationship between p16 INK 4a expression and these features of senescence, somatic inactivation of p16 INK 4a in chondrocytes of adult mice did not mitigate SASP expression and did not alter the rate of osteoarthritis (OA) with physiological aging or after destabilization of the medial meniscus. These results establish that p16 INK 4a expression is a biomarker of dysfunctional chondrocytes, but that the effects of chondrocyte senescence on OA are more likely driven by production of SASP molecules than by loss of chondrocyte replicative function.

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“…Senescent cells are mainly characterized by a stable cell cycle arrest and the appearance of features such as senescence‐associated‐β‐galactosidase activity (SA‐β‐Gal) and senescence‐associated secretory phenotype (SASP; Kuilman, Michaloglou, Mooi, & Peeper, 2010). Senescence plays a key role in many pathophysiological contexts, such as embryonic development, wound healing, cancer, and aging (He, & Sharpless, 2017). Understanding how senescence is controlled at the molecular and cellular level is therefore crucial.…”

Section: Introductionmentioning

confidence: 99%

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

Warnier

Raynard

et al. 2018

Aging Cell

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Calcium signaling is emerging as a key pathway controlling cellular senescence, a stable cell proliferation arrest playing a fundamental role in pathophysiological conditions, such as embryonic development, wound healing, cancer, and aging. However, how calcium signaling is regulated is still only partially understood. The inositol 1, 4, 5‐trisphosphate receptor type 2 (ITPR2), an endoplasmic reticulum calcium release channel, was recently shown to critically contribute to the implementation of senescence, but how ITPR2 expression is controlled is unclear. To gain insights into the regulation of ITPR2 expression, we performed an siRNA screen targeting 160 transcription factors and epigenetic regulators. Interestingly, we discovered that the retinoid X receptor alpha (RXRA), which belongs to the nuclear receptor family, represses ITPR2 expression and regulates calcium signaling though ITPR2 and the mitochondrial calcium uniporter (MCU). Knockdown of RXRA induces the production of reactive oxygen species (ROS) and DNA damage via the ITPR2‐MCU calcium signaling axis and consequently triggers cellular senescence by activating p53, whereas RXRA overexpression decreases DNA damage accumulation and then delays replicative senescence. Altogether, our work sheds light on a novel mechanism controlling calcium signaling and cellular senescence and provides new insights into the role of nuclear receptors.

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Senescence in Health and Disease

Cited by 1,162 publications

References 105 publications

Elimination of p19^ARF‐expressing cells protects against pulmonary emphysema in mice

Elimination of p19^ARF‐expressing cells protects against pulmonary emphysema in mice

Expression of p16^INK^4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

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Senescence in Health and Disease

Cited by 1,162 publications

References 105 publications

Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice

Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice

Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

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Product

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Elimination of p19^ARF‐expressing cells protects against pulmonary emphysema in mice

Elimination of p19^ARF‐expressing cells protects against pulmonary emphysema in mice

Expression of p16^INK^4a is a biomarker of chondrocyte aging but does not cause osteoarthritis