<scp>mTORC</scp>
            1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in
            <scp>IPF</scp>
            fibroblasts

Romero, Yair; Bueno, Marta; Ramı́rez, Remedios; Álvarez, Diana; Sembrat, John; Goncharova, Elena A.; Rojas, Mauricio; Selman, Moisés; Mora, Ana L.; Pardo, Annie

doi:10.1111/acel.12514

Cited by 151 publications

(132 citation statements)

References 47 publications

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“…Old and IPF lung fibroblasts have dysfunctional autophagy activity with increased LC3 puncta, p62 accumulation, and persistent activation of the mTOR pathway under starvation conditions. However, the activation of mTOR was further enhanced in IPF fibroblasts and associated with greater resistance to apoptosis (20). Altogether, these studies suggest that aberrant activation of mTOR and the resulting defective autophagy in aging IPF fibroblasts play a role in the development of lung fibrosis.…”

Section: Cellular Perturbations In the Ipf Lungmentioning

confidence: 80%

“…Analyses of autophagy activity in aging murine lungs show markers of autophagy flux blockade (17,19). Most recently, we have shown that dysfunctional autophagy activity also occurs in aging lung fibroblasts from healthy humans (20). Senescence, mitochondrial dysfunction, and insufficient autophagy in the aging lung might have implications in maladaptive responses to stress.…”

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confidence: 91%

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Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mora¹,

Bueno²,

Rojas³

2017

Journal of Clinical Investigation

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184

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 Lungmentioning

confidence: 80%

mentioning

confidence: 91%

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mora¹,

Bueno²,

Rojas³

2017

Journal of Clinical Investigation

Self Cite

184

169

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“…Based on their data, the authors suggested a protective feedback loop in which mTOR-dependent anti-inflammatory and antifibrotic regulation by SIRT1 fails in SSc, but can be functionally restored by elevating SIRT1 levels with resveratrol. Persistent activation of the mTOR pathway has also been shown in aged and IPF lung fibroblasts and linked to inhibition of autophagy, development of cellular senescence, and fibroblast resistance to apoptosis in pulmonary fibrosis [123, 124]. …”

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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“…A notable feature of IPF is the presence of apoptosis-resistant lung fibroblasts. In a recent study, investigators found that normal aging promoted resistance to apoptosis through chronic basal activation of mTORC1 signaling and resultant suppression of autophagy (18). Fibroblasts from patients with IPF demonstrated a further increase in mTORC1 signaling.…”

Section: Mtor In Disease and Agingmentioning

confidence: 99%

“…mTOR and Lung Diseases mTOR has been studied in the context of two of the major lung diseases, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), with similar findings with regard to mTOR activity. Researchers in several studies have reported that basal levels of mTORC1 and mTORC2 signaling are elevated in either IPF fibroblasts or tissue biopsies (15)(16)(17)(18). A notable feature of IPF is the presence of apoptosis-resistant lung fibroblasts.…”

Section: Mtor In Disease and Agingmentioning

confidence: 99%