Lamin A-Dependent Nuclear Defects in Human Aging

Scaffidi, Paola; Misteli, Tom

doi:10.1126/science.1127168

Cited by 1,080 publications

(1,110 citation statements)

References 14 publications

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“…These changes are exacerbated by prolonged passage in culture. Interestingly, after passage in culture, cells from aging normal individuals (>80 years) show similar changes in heterochromatin structure as HGPS individuals [98]. In sum, studies of HGPS cells are consistent with the idea that changes in chromatin structurespecifically loss of heterochromatin -may contribute to the aging phenotype.…”

Section: Progeria Cells Exhibit Accelerated Changes In Chromatinsupporting

confidence: 69%

“…HGPS cells show numerous phenotypes, including dramatic defects in nuclear envelope structure, DNA damage and repair defects, changes in gene expression and a reduced rate of proliferation [95]. Fibroblasts from HGPS cells also exhibit epigenetic defects, including decreased abundance of heterochromatic markers, such as histone H3 lysine 9 methylation (H3K9Me) and HP1 proteins [97][98][99]. These changes are exacerbated by prolonged passage in culture.…”

Section: Progeria Cells Exhibit Accelerated Changes In Chromatinmentioning

confidence: 99%

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Aging by epigenetics—A consequence of chromatin damage?

Sedivy

Gowrishankar

Adams

2008

Experimental Cell Research

142

102

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Chromatin structure is not fixed. Instead, chromatin is dynamic and is subject to extensive developmental and age-associated remodeling. In some cases, this remodeling appears to counter the aging and age-associated diseases, such as cancer, and extend organismal lifespan. However, stochastic non-deterministic changes in chromatin structure might, over time, also contribute to the break down of nuclear, cell and tissue function, and consequently aging and age-associated diseases.

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Section: Progeria Cells Exhibit Accelerated Changes In Chromatinsupporting

confidence: 69%

Section: Progeria Cells Exhibit Accelerated Changes In Chromatinmentioning

confidence: 99%

Aging by epigenetics—A consequence of chromatin damage?

Sedivy

Gowrishankar

Adams

2008

Experimental Cell Research

142

102

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“…Interestingly, it has been shown that the products of this aberrant splicing, the truncated transcript and resultant protein (named progerin), increase in number with aging in HGPS (Goldman et al ., 2004; Cao et al ., 2007; Rodriguez et al ., 2009). 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%

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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“…Many characteristics of normal aging appear to be accelerated in individuals with dominant mutations in the LMNA gene encoding A‐type lamins (Ahmed, Ikram, Bibi & Mir, 2017; Apte, Stick & Radmacher, 2017; Cenni et al., 2017; Ikeda et al., 2016; Scaffidi & Misteli, 2006). These include cardiac diseases with a broad range of arrhythmic disturbances, left ventricle dysfunction, and heart failure that show increasing penetrance with age (Captur et al., 2017; Liang, Grogan & Ackerman, 2016).…”

Section: Introductionmentioning

confidence: 99%

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

et al. 2018

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SummaryMutations in the human LMNA gene cause a collection of diseases known as laminopathies. These include myocardial diseases that exhibit age‐dependent penetrance of dysrhythmias and heart failure. The LMNA gene encodes A‐type lamins, intermediate filaments that support nuclear structure and organize the genome. Mechanisms by which mutant lamins cause age‐dependent heart defects are not well understood. To address this issue, we modeled human disease‐causing mutations in the Drosophila melanogaster Lamin C gene and expressed mutant Lamin C exclusively in the heart. This resulted in progressive cardiac dysfunction, loss of adipose tissue homeostasis, and a shortened adult lifespan. Within cardiac cells, mutant Lamin C aggregated in the cytoplasm, the CncC(Nrf2)/Keap1 redox sensing pathway was activated, mitochondria exhibited abnormal morphology, and the autophagy cargo receptor Ref2(P)/p62 was upregulated. Genetic analyses demonstrated that simultaneous over‐expression of the autophagy kinase Atg1 gene and an RNAi against CncC eliminated the cytoplasmic protein aggregates, restored cardiac function, and lengthened lifespan. These data suggest that simultaneously increasing rates of autophagy and blocking the Nrf2/Keap1 pathway are a potential therapeutic strategy for cardiac laminopathies.

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Lamin A-Dependent Nuclear Defects in Human Aging

Cited by 1,080 publications

References 14 publications

Aging by epigenetics—A consequence of chromatin damage?

Aging by epigenetics—A consequence of chromatin damage?

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

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

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