Aneuploidy analysis in fibroblasts of human premature aging syndromes by FISH during in vitro cellular aging

Premature aging of the skin is a prominent side effect of psoralen photoactivation, a treatment used widely for various skin disorders. The molecular mechanisms underlying premature aging upon psoralen photoactivation are as yet unknown. Here we show that treatment of fibroblasts with 8-methoxypsoralen (8-MOP) and subsequent ultraviolet A (UVA) irradiation resulted in a permanent switch of mitotic to stably postmitotic fibroblasts which acquired a high level of de novo expression of SA-beta-galactosidase, a marker for fibroblast senescence in vitro and in vivo. A single exposure of fibroblasts to 8-MOP/UVA resulted in a 5.8-fold up-regulation of two matrix-degrading enzymes, interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3), over a period of >120 days, while TIMP-1, the major inhibitor of MMP-1 and MMP-3, was only slightly induced. This imbalance between matrix-degrading metalloproteases and their inhibitor may lead to connective tissue damage, a hallmark of premature aging. Superoxide anion and hydrogen peroxide, but not singlet oxygen, were identified as important intermediates in the downstream signaling pathway leading to these complex fibroblast responses upon psoralen photoactivation. Collectively, the end phenotype induced upon psoralen photoactivation shares several criteria of senescent cells. In the absence of detailed molecular data on what constitutes normal aging, it is difficult to decide whether the changes reported here reflect mechanisms underlying normal cellular aging/senescence or rather produce a mimic of cellular aging/senescence by quite different pathways.

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The impaired transcription factor AP-1 DNA binding activity in lymphocytes derived from subjects with some symptoms of premature aging.

Acta Biochimica Polonica ◽

10.18388/abp.1993_4828 ◽

1993 ◽

Vol 40 (2) ◽

pp. 269-272 ◽

Cited By ~ 6

Author(s):

E Sikora ◽

E Radziszewska ◽

T Kmieć ◽

D Maślińska

Keyword(s):

Dna Binding ◽

Cellular Senescence ◽

Molecular Mechanisms ◽

Replicative Senescence ◽

Binding Activity ◽

Premature Aging ◽

Mobility Shift ◽

Dna Binding Activity ◽

Premature Aging Syndromes

The study of human disorders known as premature aging syndromes may provide insight into the mechanisms of cellular senescence. The main feature of cellular senescence in vitro is cessation of cell proliferation. Down syndrome (DS) and neuronal ceroid-lypofuscinosis (NCL) are clinically characterized by the premature onset of numerous features normally associated with human aging. Phytohemagglutinin stimulated lymphocytes derived from DS subjects showed a statistically significant diminished proliferation capacity in comparison with lymphocytes derived from NCL and healthy individuals. We demonstrated, by applying the electrophoretic mobility shift assay, slightly impaired AP-1 DNA binding activity in NCL lymphocytes and strong in DS ones. Our results showed that the same molecular mechanisms of proliferation cessation could exist in fibroblasts characterized by replicative senescence and in lymphocytes derived from individuals with premature aging syndromes (Down).

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The role of telomeres and vitamin D in cellular aging and age-related diseases

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2014-1184 ◽

2015 ◽

Vol 53 (11) ◽

Cited By ~ 15

Author(s):

Irene Pusceddu ◽

Christopher-John L. Farrell ◽

Angela Maria Di Pierro ◽

Erika Jani ◽

Wolfgang Herrmann ◽

...

Keyword(s):

Vitamin D ◽

Genomic Stability ◽

Cellular Aging ◽

Premature Aging ◽

Age Related ◽

Complex Biological Process ◽

Increased Risk ◽

Telomere Biology

AbstractAging is a complex biological process characterized by a progressive decline of organ functions leading to an increased risk of age-associated diseases and death. Decades of intensive research have identified a range of molecular and biochemical pathways contributing to aging. However, many aspects regarding the regulation and interplay of these pathways are insufficiently understood. Telomere dysfunction and genomic instability appear to be of critical importance for aging at a cellular level. For example, age-related diseases and premature aging syndromes are frequently associated with telomere shortening. Telomeres are repetitive nucleotide sequences that together with the associated sheltrin complex protect the ends of chromosomes and maintain genomic stability. Recent studies suggest that micronutrients, such as vitamin D, folate and vitamin B12, are involved in telomere biology and cellular aging. In particular, vitamin D is important for a range of vital cellular processes including cellular differentiation, proliferation and apoptosis. As a result of the multiple functions of vitamin D it has been speculated that vitamin D might play a role in telomere biology and genomic stability. Here we review existing knowledge about the link between telomere biology and cellular aging with a focus on the role of vitamin D. We searched the literature up to November 2014 for human studies, animal models and in vitro experiments that addressed this topic.

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Can Be miR-126-3p a Biomarker of Premature Aging? An Ex Vivo and In Vitro Study in Fabry Disease

Cells ◽

10.3390/cells10020356 ◽

2021 ◽

Vol 10 (2) ◽

pp. 356 ◽

Cited By ~ 1

Author(s):

Alessia Lo Curto ◽

Simona Taverna ◽

Maria Assunta Costa ◽

Rosa Passantino ◽

Giuseppa Augello ◽

...

Keyword(s):

Endothelial Cells ◽

Fabry Disease ◽

Healthy Subjects ◽

Aging Process ◽

Replicative Senescence ◽

Ex Vivo ◽

Umbilical Vein ◽

Quantitative Polymerase Chain Reaction ◽

Premature Aging

Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by lysosomal accumulation of glycosphingolipids in a wide variety of cytotypes, including endothelial cells (ECs). FD patients experience a significantly reduced life expectancy compared to the general population; therefore, the association with a premature aging process would be plausible. To assess this hypothesis, miR-126-3p, a senescence-associated microRNA (SA-miRNAs), was considered as an aging biomarker. The levels of miR-126-3p contained in small extracellular vesicles (sEVs), with about 130 nm of diameter, were measured in FD patients and healthy subjects divided into age classes, in vitro, in human umbilical vein endothelial cells (HUVECs) “young” and undergoing replicative senescence, through a quantitative polymerase chain reaction (qPCR) approach. We confirmed that, in vivo, circulating miR-126 levels physiologically increase with age. In vitro, miR-126 augments in HUVECs underwent replicative senescence. We observed that FD patients are characterized by higher miR-126-3p levels in sEVs, compared to age-matched healthy subjects. We also explored, in vitro, the effect on ECs of glycosphingolipids that are typically accumulated in FD patients. We observed that FD storage substances induced in HUVECs premature senescence and increased of miR-126-3p levels. This study reinforces the hypothesis that FD may aggravate the normal aging process.

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Signal Transducer and Activator of Transcription 3 (STAT3) Suppresses STAT1/Interferon Signaling Pathway and Inflammation in Senescent Preadipocytes

Antioxidants ◽

10.3390/antiox10020334 ◽

2021 ◽

Vol 10 (2) ◽

pp. 334

Author(s):

Aisha Y. Madani ◽

Yasser Majeed ◽

Houari B. Abdesselem ◽

Maha V. Agha ◽

Muneera Vakayil ◽

...

Keyword(s):

Adipose Tissue ◽

Molecular Mechanisms ◽

Adenosine Monophosphate ◽

Human Adipose Tissue ◽

Premature Aging ◽

Guanosine Monophosphate ◽

Negative Regulator ◽

Signal Transducer ◽

Interferon Signaling

Obesity promotes premature aging and dysfunction of white adipose tissue (WAT) through the accumulation of cellular senescence. The senescent cells burden in WAT has been linked to inflammation, insulin-resistance (IR), and type 2 diabetes (T2D). There is limited knowledge about molecular mechanisms that sustain inflammation in obese states. Here, we describe a robust and physiologically relevant in vitro system to trigger senescence in mouse 3T3-L1 preadipocytes. By employing transcriptomics analyses, we discovered up-regulation of key pro-inflammatory molecules and activation of interferon/signal transducer and activator of transcription (STAT)1/3 signaling in senescent preadipocytes, and expression of downstream targets was induced in epididymal WAT of obese mice, and obese human adipose tissue. To test the relevance of STAT1/3 signaling to preadipocyte senescence, we used Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology to delete STAT1/3 and discovered that STAT1 promoted growth arrest and cooperated with cyclic Guanosine Monophosphate-Adenosine Monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) to drive the expression of interferon β (IFNβ), C-X-C motif chemokine ligand 10 (CXCL10), and interferon signaling-related genes. In contrast, we discovered that STAT3 was a negative regulator of STAT1/cGAS-STING signaling—it suppressed senescence and inflammation. These data provide insights into how STAT1/STAT3 signaling coordinates senescence and inflammation through functional interactions with the cGAS/STING pathway.

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Understanding Vascular Diseases: Lessons From Premature Aging Syndromes

Canadian Journal of Cardiology ◽

10.1016/j.cjca.2015.12.003 ◽

2016 ◽

Vol 32 (5) ◽

pp. 650-658 ◽

Cited By ~ 3

Author(s):

Yuichi Ikeda ◽

Hidetoshi Kumagai ◽

Yoshihiro Motozawa ◽

Jun-ichi Suzuki ◽

Hiroshi Akazawa ◽

...

Keyword(s):

Vascular Diseases ◽

Premature Aging ◽

Premature Aging Syndromes

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Assessment of Long-Term in vitro Multiplied Human Wharton’s Jelly-Derived Mesenchymal Stem Cells prior to Their Use in Clinical Administration

Cells Tissues Organs ◽

10.1159/000517423 ◽

2021 ◽

pp. 1-11

Author(s):

Urvi Panwar ◽

Kanchan Mishra ◽

Parizad Patel ◽

Sumit Bharadva ◽

Salil Vaniawala ◽

...

Keyword(s):

Telomere Length ◽

Replicative Senescence ◽

Ex Vivo ◽

Wharton’S Jelly ◽

Cellular Aging ◽

Human Umbilical Cord ◽

Surface Markers ◽

Wharton's Jelly ◽

Ex Vivo Culture

The quantity of mesenchymal stem/stromal cells (MSCs) required for a particular therapy demands their subsequent expansion through ex vivo culture. During in vitro multiplication, they undergo replicative senescence which may alter their genetic stability. Therefore, this study was aimed to analyze cellular, molecular, and chromosomal alterations in Wharton’s jelly-derived MSCs (WJ-MSCs) during their in vitro sequential passages, where WJ-MSCs were sequentially passaged up to P14 and cells were evaluated at an interval of P2, P6, P10, and P14. They were examined for their morphology, tumorigenicity, surface markers, stemness markers, DNA damage, chromosomal aberration, and telomere length. We have processed five full-term delivered human umbilical cord samples to obtain WJ-MSCs. Morphological appearance observed at initial stages was small fine spindle-shaped WJ-MSCs which were transformed to flat, long, and broader cells in later passages. The cell proliferation rate was gradually decreased after the 10th passage. WJ-MSCs have expressed stemness markers OCT-4 and NANOG, while they showed high expression of positive surface markers CD90 and CD105 and lower expression of CD34 and CD45. They were non-tumorigenic with slow cellular aging during subsequent passages. There was no chromosomal abnormality up to the 14th passage, while increase in comet score and decrease in telomere length were observed in later passages. Hence, our study suggests that early and middle passaged (less than P10) WJ-MSCs are good candidates for clinical administration for treatment.

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Accelerated Aging of Dermal Fibroblast-like Cells From the Senescence-Accelerated Mouse (SAM): Acceleration of Changes in DNA Ploidy Associated With In Vitro Cellular Aging

The Journals of Gerontology Series A ◽

10.1093/gerona/53a.1.b11 ◽

1998 ◽

Vol 53A (1) ◽

pp. B11-B18 ◽

Cited By ~ 18

Author(s):

H. Fujisawa ◽

T. Nishikawa ◽

B.-H. Zhu ◽

N. Takeda ◽

H. Jujo ◽

...

Keyword(s):

Dna Ploidy ◽

Dermal Fibroblast ◽

Accelerated Aging ◽

Cellular Aging ◽

Senescence Accelerated Mouse

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Aging, cellular senescence and cancer: epigenetic alterations and nuclear remodeling

Epigenetics, Nuclear Organization & Gene Function ◽

10.1093/oso/9780198831204.003.0021 ◽

2019 ◽

pp. 238-253

Author(s):

John C. Lucchesi

Keyword(s):

Histone Modifications ◽

Cellular Senescence ◽

Aging Process ◽

Nuclear Architecture ◽

Gene Mutations ◽

Histone Variants ◽

Premature Aging ◽

Model Organisms ◽

Premature Aging Syndromes ◽

Nuclear Remodeling

Epigenetic modifications correlated with aging and oncogenesis are changes in the pattern of DNA methylation and of histone modifications, and changes in the level of histone variants (H3.3, macroH2A, H2A.Z) and gene mutations. The sirtuins are a set of highly conserved protein deacetylases of particular significance to the aging process. Many cancer types are found to carry mutations in chromatin-modifying genes such as those encoding methyl or acetyl transferases, affecting the histone modifications of promoters and enhancers. The aging process and oncogenesis present a number of changes in the nuclear architecture. Mutations in the lamina-coding genes lead to premature aging syndromes. Mutations in remodeling complexes are found in different cancers. Modifications that affect the architectural protein binding sites at topologically associating domain (TAD) borders can cause the merging of neighboring TADs. The levels of short non-coding RNAs (sncRNAs) are altered in model organisms and are associated with cancer. Changes in the position of chromosome territories often occur in tumor cells. Nevertheless, cellular senescence, due mostly to the absence of telomerase, represents a mechanism of tumor suppression.

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