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NAD Regulation of Cellular Senescence Is Mediated by Telomerase Reverse Transcriptase Expression
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A4641 - NAD Regulation of Cellular Senescence Is Mediated by Telomerase Reverse Transcriptase Expression
Author Block: T. Liu, J. Lu, B. Hu, Z. Wu, M. Harada, Y. Zhao, S. H. Phan; Pathology, University of Michigan, Ann Arbor, MI, United States.
Aging can be considered a risk factor for development of chronic fibrotic diseases, including idiopathic pulmonary fibrosis (IPF), since they primarily affect the older age group, where increased numbers of fibroblasts constitute fibrotic foci. Cellular senescence is a characteristic of organismal aging, and its occurrence in fibrotic lung suggests a potential pathogenic role. There is evidence that apoptosis-resistant senescent fibroblasts accumulates in fibrotic lung, however the mechanism regulating cellular senescence in chronic fibrosis is unclear. In this study telomerase reverse transcriptase (TERT) deficient fibroblasts exhibited greater susceptibility to cellular senescence. To further investigate the potential role of TERT in regulating cellular senescence, oxidative stress(H2O2)-induced senescence (OIS) was first evaluated in human foreskin fibroblasts (BJ) and compared to that in the same cells in which TERT is stably overexpressed (BJ5ta). The results showed that TERT overexpression in BJ5ta cells afforded protection from OIS, while normal BJ fibroblasts exhibited significant senescent phenomena revealed by induction of senescence biomarkers p16 and p21, and by increased senescence associated β-galactosidase (β-gal) activity. In addition, senescence-associated secretory phenotype (SASP) induced in BJ cells as measured by IL-6 mRNA level was also not evident in TERT-overexpressing BJ5ta cells. NAD is an essential co-substrate for Sirt1 deacetylase, a TERT inducer and senescence inhibitor. To explore the potential impact of NAD on TERT regulation of senescence, cellular NAD level was increased by supplementation with exogenous nicotinamide mononucleotide (NMN). The results showed that NMN was able to inhibit OIS, which was associated with increased TERT expression in BJ cells. Consistently, elevated NAD level by treatment with NMN caused significant enhancement of bleomycin-induction of TERT in injured lung, whereas senescence marker p21 and p16 expression was markedly reduced. These findings suggested that NAD afforded protection from OIS by induction of TERT, which resulted in repression of p16 and p21. Since Sirt1, which requires NAD for activity, is known to induce TERT, it is likely that the NAD effect on TERT expression is mediated through increased Sirt1 activity. Thus any attempt at altering NAD levels to regulate Sirt1 activity should consider this potential effect on TERT induction.
Author Block: T. Liu, J. Lu, B. Hu, Z. Wu, M. Harada, Y. Zhao, S. H. Phan; Pathology, University of Michigan, Ann Arbor, MI, United States.
Aging can be considered a risk factor for development of chronic fibrotic diseases, including idiopathic pulmonary fibrosis (IPF), since they primarily affect the older age group, where increased numbers of fibroblasts constitute fibrotic foci. Cellular senescence is a characteristic of organismal aging, and its occurrence in fibrotic lung suggests a potential pathogenic role. There is evidence that apoptosis-resistant senescent fibroblasts accumulates in fibrotic lung, however the mechanism regulating cellular senescence in chronic fibrosis is unclear. In this study telomerase reverse transcriptase (TERT) deficient fibroblasts exhibited greater susceptibility to cellular senescence. To further investigate the potential role of TERT in regulating cellular senescence, oxidative stress(H2O2)-induced senescence (OIS) was first evaluated in human foreskin fibroblasts (BJ) and compared to that in the same cells in which TERT is stably overexpressed (BJ5ta). The results showed that TERT overexpression in BJ5ta cells afforded protection from OIS, while normal BJ fibroblasts exhibited significant senescent phenomena revealed by induction of senescence biomarkers p16 and p21, and by increased senescence associated β-galactosidase (β-gal) activity. In addition, senescence-associated secretory phenotype (SASP) induced in BJ cells as measured by IL-6 mRNA level was also not evident in TERT-overexpressing BJ5ta cells. NAD is an essential co-substrate for Sirt1 deacetylase, a TERT inducer and senescence inhibitor. To explore the potential impact of NAD on TERT regulation of senescence, cellular NAD level was increased by supplementation with exogenous nicotinamide mononucleotide (NMN). The results showed that NMN was able to inhibit OIS, which was associated with increased TERT expression in BJ cells. Consistently, elevated NAD level by treatment with NMN caused significant enhancement of bleomycin-induction of TERT in injured lung, whereas senescence marker p21 and p16 expression was markedly reduced. These findings suggested that NAD afforded protection from OIS by induction of TERT, which resulted in repression of p16 and p21. Since Sirt1, which requires NAD for activity, is known to induce TERT, it is likely that the NAD effect on TERT expression is mediated through increased Sirt1 activity. Thus any attempt at altering NAD levels to regulate Sirt1 activity should consider this potential effect on TERT induction.
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