Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts

Cao, Kan; Blair, Cecilia D.; Faddah, Dina A.; Kieckhaefer, Julia E.; Olive, Michelle; Erdos, Michael R.; Nabel, Elizabeth G.; Collins, Francis S.

doi:10.1172/jci43578

Cited by 276 publications

(250 citation statements)

References 55 publications

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“…6A‐1). We found these differentially expressed genes overlapped significantly with previous microarray and RNA‐seq studies (Cao et al ., 2011a; McCord et al ., 2013). When normal + vehicle vs. normal + MB was compared, only a few genes showed significant expression changes (up/down: 0.19%/0.14%, Fig.…”

Section: Resultsmentioning

confidence: 99%

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

et al. 2015

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SummaryHutchinson–Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single‐nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high‐resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC‐1α, a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial‐targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS.

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Section: Resultsmentioning

confidence: 99%

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

et al. 2015

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“…This trend is evident in both wild‐type mice during physiological aging and in a premature aging mouse model, suggesting that alternative splicing might be more important in the aging process than has previously been noted. Our results are in agreement with those of other recent studies that have shown an effect of age on AS in human brain (Tollervey et al ., 2011; Mazin et al ., 2013), human peripheral blood leukocytes (Harries et al ., 2011), and senescent fibroblasts induced by telomere shortening (Cao et al ., 2011). To our knowledge, this is the first study to show that the amount of age‐related AS increases with more advanced age (4–18 months compared to 4–28 months) and in several tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, our results showed that during normal aging, several components of the mouse spliceosome pathway were affected, meaning that the splicing machinery would in particular be affected by age‐related AS, which is in agreement with another in vivo study that showed in human blood an effect of age on RNA processing (Harries et al ., 2011). However, AS genes in senescent fibroblasts induced by telomere shortening have been reported to be involved in remodeling of the cytoskeleton, but not in RNA processing (Cao et al ., 2011). This disagreement might be related to the differences in the origin of the cells (Gaidatzis et al ., 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Cao et al . (2011) showed that telomere shortening induced extensive AS and increased progerin production in normal senescent cells. However, they did not show evidence that AS was directly induced by progerin, while our results showed that sustained progerin expression is associated with increased AS in HGPS.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, several reports have found progerin, and increasing levels of progerin, in normal cells over the course of normal aging (Scaffidi & Misteli, 2006; McClintock et al ., 2007; Cao et al ., 2007; Rodriguez et al ., 2009), which suggests a similar genetic mechanism in HGPS and normal aging. Moreover, genome‐scale expression profiling in cells from HGPS patients, as well as in physiological aging, has revealed widespread transcriptional misregulation in multiple mammalian tissues (Ly et al ., 2000; Csoka et al ., 2004; Zahn et al ., 2007; Scaffidi & Misteli, 2008; Cao et al ., 2011; McCord et al ., 2013). …”

Section: Introductionmentioning

confidence: 99%

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Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

et al. 2015

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SummaryAlternative splicing (AS) is a key regulatory mechanism for the development of different tissues; however, not much is known about changes to alternative splicing during aging. Splicing events may become more frequent and widespread genome‐wide as tissues age and the splicing machinery stringency decreases. Using skin, skeletal muscle, bone, thymus, and white adipose tissue from wild‐type C57BL6/J male mice (4 and 18 months old), we examined the effect of age on splicing by AS analysis of the differential exon usage of the genome. The results identified a considerable number of AS genes in skeletal muscle, thymus, bone, and white adipose tissue between the different age groups (ranging from 27 to 246 AS genes corresponding to 0.3–3.2% of the total number of genes analyzed). For skin, skeletal muscle, and bone, we included a later age group (28 months old) that showed that the number of alternatively spliced genes increased with age in all three tissues (P < 0.01). Analysis of alternatively spliced genes across all tissues by gene ontology and pathway analysis identified 158 genes involved in RNA processing. Additional analysis of AS in a mouse model for the premature aging disease Hutchinson–Gilford progeria syndrome was performed. The results show that expression of the mutant protein, progerin, is associated with an impaired developmental splicing. As progerin accumulates, the number of genes with AS increases compared to in wild‐type skin. Our results indicate the existence of a mechanism for increased AS during aging in several tissues, emphasizing that AS has a more important role in the aging process than previously known.

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Cellular Basis of Laminopathies

Cao

2012

Encyclopedia of Life Sciences

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The nuclear lamina is the main architectural component of a eukaryotic nucleus. More than an inert scaffold, the lamina is essential for maintaining proper nuclear organisation, epigenetic composition, transcriptional regulation and cell cycle progression. Mutations within lamin genes lead to a wide range of diseases known as laminopathies, among which the striking premature aging disease Hutchinson–Gilford progeria syndrome (HGPS) is the most well known. Studies regarding the cellular basis of laminopathies have advanced our knowledge of the nuclear lamina and yielded remarkable insights into the process of normal human aging. Understanding the molecular mechanisms responsible for disease manifestations has also led to the development of novel therapeutic strategies to address lamina‐related diseases. Ultimately, scientists and clinicians seek to provide treatment options to laminopathy patients to alleviate symptoms and perhaps to cure these diseases in the future. Key Concepts: Mutations in genes encoding lamin proteins lead to a wide range of diseases known as laminopathies. The nuclear lamina plays essential roles in maintaining nuclear architecture, chromatin organisation, cellular differentiation and gene expression. Studies of the molecular mechanisms underlying laminopathies have led to advances in the understanding of lamin structure and function. Progerin, the mutant form of lamin A expressed in Hutchinson–Gilford progeria syndrome, is also present in normal individuals, albeit at a low level. Recent advances have led to the development of noval therapeutic options for patients suffering from HGPS.

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Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts

Cited by 276 publications

References 55 publications

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

Cellular Basis of Laminopathies

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