Cellular senescence-like features of lung fibroblasts derived from idiopathic pulmonary fibrosis patients

Yanai, Hagai; Shteinberg, Albert; Porat, Ziv; Budovsky, Arie; Braiman, Alex; Zeische, Rolf; Fraifeld, Vadim E.

doi:10.18632/aging.100807

Cited by 154 publications

(116 citation statements)

References 41 publications

(57 reference statements)

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“…Consistent with studies in mouse models, fibroblasts and lung epithelial cells from IPF lungs express markers of senescence, including positive β-gal staining and p21 expression (23,71,78). However, the majority of the current studies with human lung fibroblasts lack appropriate age-matched controls to determine whether the senescent and profibrotic phenotype is related to advanced age.…”

Section: Cellular Perturbations In the Ipf Lungsupporting

confidence: 53%

“…OGG1 is a DNA repair differently (Table 3). For example, senescence can be responsible for exhaustion of stem cells (69), secretion of inflammatory mediators in immune cells and fibroblasts (70), and increased myofibroblast differentiation in lung fibroblasts (71). Stressinduced senescence has been observed in isolated mouse lung fibroblasts from fibrotic lungs, although their proliferative capacity vary between studies.…”

Section: Cellular Perturbations In the Ipf Lungmentioning

confidence: 99%

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Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mora¹,

Bueno²,

Rojas³

2017

Journal of Clinical Investigation

183

169

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One of the most remarkable medical accomplishments in the last century has been the increasing longevity of the human population. A decrease in birth rates, accompanied by a reduction in mortality among the elderly population, has collectively increased the percentage of the aged population, particularly in developed countries. Globally, it is estimated that the proportion of the population over the age of 60 will increase from 11% to 22% by 2050, and 28% by 2100. Currently, 18% of the US population is over 60 years of age (57 million), which is predicted to rise to 27% (107 million) in 2050 and up to 31% (149 million) by 2100 (1). The aging population has propelled an increase in the overall prevalence of chronic conditions. Several lung diseases, including acute lung injury and asthma, and some infectious diseases, such as pneumonia, increase in severity and mortality with age. Additionally, there has been a significant increase in incidence of chronic lung diseases -including chronic obstructive pulmonary disease, most forms of lung cancer, and idiopathic pulmonary fibrosis (IPF) -resulting in aging-related increases in prevalence.IPF is the most common form of idiopathic interstitial lung diseases. Its overall incidence in the US is 7 to 17 per 100,000 persons with a prevalence between 13.2 and 63 per 100,000 persons (2). A 1996 study initially demonstrated a higher incidence and prevalence of IPF in patients over 65 (3). These observations were confirmed more recently by Raghu et al. (4) and others, using both broad and narrow case-finding criteria for IPF diagnosis. These studies estimated that in the US, the prevalence of IPF increases with age, ranging from 4 per 100,000 for population aged between 18 and 34 years old to 227.2 per 100,000 among those 75 or older (4). This aging-related increase in cumulative incidence and prevalence of IPF has been corroborated by several studies that include populations in Europe and Asia (5-9). Accordingly, the median age at diagnosis of sporadic IPF ranges between 50 and 85 years old, and patients younger than 50 are more commonly associated with familial, rather than sporadic, forms of the disease (2). Mortality rates from IPF are steadily increasing worldwide, and a positive association has also been observed with advanced age (10). Examination of US government health insurance data for people aged 65 and older shows an increasing prevalence of IPF among older age groups (11). These studies confirm the growing concern that aging, and consequently age-related diseases, will drive up health care expenditures. As the elderly population in developed countries is expected to double in the next 25 years, there is an urgent need to understand the pathogenesis of IPF and develop interventions to attenuate or reverse lung fibrosis. The physiology of aging and the lungEvolutionary theories of aging include the concept of selection shadow that permits the accumulation of mutations with late deleterious effects, and the theory of antagonistic pleiotropy, which supports the sele...

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Section: Cellular Perturbations In the Ipf Lungsupporting

confidence: 53%

Section: Cellular Perturbations In the Ipf Lungmentioning

confidence: 99%

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mora¹,

Bueno²,

Rojas³

2017

Journal of Clinical Investigation

183

169

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“…Moreover, senescent cells might be harmful and contribute to tissue remodelling, ageing and age-related diseases. In this context, alveolar epithelial and lung fibroblasts with a senescent phenotype are a prominent feature of IPF [111][112][113][114][115] .…”

Section: Senescence and Saspmentioning

confidence: 99%

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

290

212

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Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches.Fibrosis as a pathogenic mechanism occurs in numerous organs and diseases. Fibrosis results from abnormal tissue repair and is associated with persistent and/or severe tissue damage and cellular stress. Epithelial and/or endothelial injury caused by various insults triggers interrelated wound-healing pathways to restore homeostasis 1 . Failure to adequately contain or eliminate inciting factors can exacerbate inflammation and chronic woundCorrespondence to A.L.M. anamora@pitt.edu. Competing interests statementThe authors declare competing interests: see Web version for details. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript healing responses, resulting in continued tissue damage and inadequate regeneration and, ultimately, fibrosis 2 . Although their aetiology and causative mechanisms differ, the various fibrotic diseases all have abnormal and exaggerated accumulation of extracellular matrix (ECM) components, mainly fibrillar collagens. The resulting fibrosis disturbs the normal architecture of affected organs, which ultimately leads to their dysfunction and failure. Nearly 45% of deaths in the developed world are attributable to some type of chronic fibroproliferative disease, including idiopathic pulmonary fibrosis (IPF) and end-stage fibrotic liver, kidney and heart disease 2 . The progressive nature of these diseases and the absence of effective treatments mean that a better understanding of the cellular and molecular mechanisms that contribute to the development of fibrosis is needed.Although IPF was originally thought to be an inflammation-driven disorder, clinical trials with a combination of anti-inflammatory drugs (prednisone, azathioprine and N-acetyl-Lcysteine (NAC)), failed to improve outcomes and instead increased mortality 3 . In 2014, two drugs, pirfenidone, a drug with poorly understood mechanisms, and nintedanib, a tyrosine kinase inhibitor, were approved for the treatment of IPF ...

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“…Recently, a new paradigm that helps explain the increased prevalence of fibrosis with aging has emerged, suggesting that fibrosis results from the accumulation and decreased turnover of senescent fibroblasts. Fibroblasts from patients with IPF have decreased proliferation and apoptosis than normal fibroblasts, are more resistant to oxidative stress, and exhibit morphological features of cellular senescence [127, 128]. Markers of cellular senescence such as β-galactosidase, p16, and p21 are increased in fibroblasts from patients with IPF and in murine lung fibrosis [128, 129], and the secretome (SASP) of senescent fibroblasts is profibrotic [129].…”

Section: Sirtuins and Sclerodermamentioning

confidence: 99%

Sirtuins and Accelerated Aging in Scleroderma

Wyman

Atamas

2018

Curr Rheumatol Rep

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Purpose of Review Premature activation of aging-associated molecular mechanisms is emerging as an important contributor to many diseases, including scleroderma. Among central regulators of the aging process are a group of histone deacetylases called sirtuins (SIRTs). Recent findings implicate these molecules as pathophysiological players in scleroderma skin and lung fibrosis. The goal of this article is to review recent studies on the involvement of SIRTs in scleroderma from the perspective of aging-related molecular mechanisms. Recent Findings Despite a degree of controversy in this rapidly developing field, the majority of data suggest that SIRT levels are decreased in tissues from patients with scleroderma compared to healthy controls as well as in animal models of scleroderma. Molecular studies reveal several mechanisms through which declining SIRT levels contribute to fibrosis, with the most attention given to modulation of the TGF-β signaling pathway. Activation of SIRTs in cell culture and in animal models elicits antifibrotic effects. Summary Declining SIRT levels and activity are emerging as pathophysiological contributors to scleroderma. Restoration of SIRTs may be therapeutic in patients with scleroderma.

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Cellular senescence-like features of lung fibroblasts derived from idiopathic pulmonary fibrosis patients

Cited by 154 publications

References 41 publications

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Sirtuins and Accelerated Aging in Scleroderma

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