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Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models.Npj Aging May 2023Cellular senescence is known to play a role in age-related skin function deterioration which potentially influences longevity. Here, a two-step phenotypic screening was...
Cellular senescence is known to play a role in age-related skin function deterioration which potentially influences longevity. Here, a two-step phenotypic screening was performed to identify senotherapeutic peptides, leading to the identification of Peptide (Pep) 14. Pep 14 effectively decreased human dermal fibroblast senescence burden induced by Hutchinson-Gilford Progeria Syndrome (HGPS), chronological aging, ultraviolet-B radiation (UVB), and etoposide treatment, without inducing significant toxicity. Pep 14 functions via modulation of PP2A, an understudied holoenzyme that promotes genomic stability and is involved in DNA repair and senescence pathways. At the single-cell level, Pep 14 modulates genes that prevent senescence progression by arresting the cell cycle and enhancing DNA repair, which consequently reduce the number of cells progressing to late senescence. When applied on aged ex vivo skin, Pep 14 promoted a healthy skin phenotype with structural and molecular resemblance to young ex vivo skin, decreased the expression of senescence markers, including SASP, and reduced the DNA methylation age. In summary, this work shows the safe reduction of the biological age of ex vivo human skins by a senomorphic peptide.
PubMed: 37217561
DOI: 10.1038/s41514-023-00109-1 -
Cell Death & Disease May 2023Osteoarthritis (OA) is an age-related degenerative disease without disease-modifying therapy. The lack of aging-induced osteoarthritis models makes the discovery of...
Osteoarthritis (OA) is an age-related degenerative disease without disease-modifying therapy. The lack of aging-induced osteoarthritis models makes the discovery of therapeutic drugs more challenging. The deficiency of ZMPSTE24 could induce Hutchinson-Gilford progeria syndrome (HGPS), a genetic disorder of rapid aging. However, the relationship between HGPS and OA remains unclear. Our results found that the expression of Zmpste24 was decreased in the articular cartilage during the aging process. Zmpste24 knockout mice, Prx1-Cre; Zmpste24 mice and Col2-CreERT2; Zmpste24 mice displayed OA phenotype. Loss of Zmpste24 in articular cartilage could exacerbate the occurrence and development of osteoarthritis. Transcriptome sequencing revealed that deletion of Zmpste24 or accumulation of progerin affects chondrocyte metabolism, inhibits cell proliferation and promotes cell senescence. Using this animal model, we elucidate the upregulation of H3K27me3 during chondrocyte senescence and discover the molecular mechanism by which lamin A mutant stabilizes EZH2 expression. The construction of aging-induced osteoarthritis models and the elucidation of the signaling pathways and molecular mechanisms of articular chondrocyte senescence would benefit the discovery and development of new drugs for OA.
Topics: Mice; Animals; Cartilage, Articular; Epigenesis, Genetic; Metalloendopeptidases; Aging; Progeria; Cellular Senescence; Mice, Knockout; Osteoarthritis; Lamin Type A; Membrane Proteins
PubMed: 37217512
DOI: 10.1038/s41419-023-05856-3 -
Cell Reports May 2023One of the major cellular mechanisms to ensure cellular protein homeostasis is the endoplasmic reticulum (ER) stress response. This pathway is triggered by accumulation...
One of the major cellular mechanisms to ensure cellular protein homeostasis is the endoplasmic reticulum (ER) stress response. This pathway is triggered by accumulation of misfolded proteins in the ER lumen. The ER stress response is also activated in the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). Here, we explore the mechanism of activation of the ER stress response in HGPS. We find that aggregation of the diseases-causing progerin protein at the nuclear envelope triggers ER stress. Induction of ER stress is dependent on the inner nuclear membrane protein SUN2 and its ability to cluster in the nuclear membrane. Our observations suggest that the presence of nucleoplasmic protein aggregates can be sensed, and signaled to the ER lumen, via clustering of SUN2. These results identify a mechanism of communication between the nucleus and the ER and provide insight into the molecular disease mechanisms of HGPS.
Topics: Humans; Aging, Premature; Nuclear Envelope; Cell Nucleus; Progeria; Membrane Proteins; Endoplasmic Reticulum Stress; Lamin Type A; Intracellular Signaling Peptides and Proteins
PubMed: 37210724
DOI: 10.1016/j.celrep.2023.112534 -
JNMA; Journal of the Nepal Medical... Mar 2023Early canities are the premature greying of hair before the age of 25 years in Asians. The condition is a matter of concern for young adults aesthetically. This study...
INTRODUCTION
Early canities are the premature greying of hair before the age of 25 years in Asians. The condition is a matter of concern for young adults aesthetically. This study aimed to find out the prevalence of early canities among undergraduate medical students of a medical college.
METHODS
A descriptive cross-sectional study was carried out from 1 December 2021 to 30 June 2022 among undergraduate medical students at a medical college. The study was conducted after receiving ethical approval from the Institutional Review Committee [Reference number: 146(6-11)C-2 078/079]. The participants with ages less than 25 years without a history of vitiligo, intake of chemotherapeutic drugs, progeria, pangeria and recent dyeing of hair were enrolled. A convenience sampling method was used. Point estimate and 95% Confidence Interval were calculated.
RESULTS
Out of 235 students, 95 (40.42%) (34.15-46.69, 95% Confidence Interval) had early canities. The most prevalent premature greying was grade I early canities i.e.79 (83.15%) of participants. Among the participants with early canities, 56 (58.94%) were male, 41 (43.15%) had a positive family history for early canities, 67 (70.52%) had normal body mass index and 38 (40%) had O+ve blood group.
CONCLUSIONS
The prevalence of early canities among undergraduate medical students was lower than in other studies done in similar settings. The grade I early canities was seen more among the participants with premature greying of hair.
KEYWORDS
epidemiology; hair colour; medical students; physiology.
Topics: Young Adult; Male; Humans; Adult; Female; Students, Medical; Cross-Sectional Studies; Hair; Coloring Agents; Research Design
PubMed: 37203960
DOI: 10.31729/jnma.7961 -
Nuclear softening mediated by Sun2 suppression delays mechanical stress-induced cellular senescence.Cell Death Discovery May 2023Nuclear decoupling and softening are the main cellular mechanisms to resist mechanical stress-induced nuclear/DNA damage, however, its molecular mechanisms remain much...
Nuclear decoupling and softening are the main cellular mechanisms to resist mechanical stress-induced nuclear/DNA damage, however, its molecular mechanisms remain much unknown. Our recent study of Hutchinson-Gilford progeria syndrome (HGPS) disease revealed the role of nuclear membrane protein Sun2 in mediating nuclear damages and cellular senescence in progeria cells. However, the potential role of Sun2 in mechanical stress-induced nuclear damage and its correlation with nuclear decoupling and softening is still not clear. By applying cyclic mechanical stretch to mesenchymal stromal cells (MSCs) of WT and Zmpset24 mice (Z24, a model for HGPS), we observed much increased nuclear damage in Z24 MSCs, which also featured elevated Sun2 expression, RhoA activation, F-actin polymerization and nuclear stiffness, indicating the compromised nuclear decoupling capacity. Suppression of Sun2 with siRNA effectively reduced nuclear/DNA damages caused by mechanical stretch, which was mediated by increased nuclear decoupling and softening, and consequently improved nuclear deformability. Our results reveal that Sun2 is greatly involved in mediating mechanical stress-induced nuclear damage by regulating nuclear mechanical properties, and Sun2 suppression can be a novel therapeutic target for treating progeria aging or aging-related diseases.
PubMed: 37198162
DOI: 10.1038/s41420-023-01467-1 -
IScience May 2023Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary artery pressure caused by pathological pulmonary artery...
Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary artery pressure caused by pathological pulmonary artery remodeling. Here, we demonstrate that endothelial cell (EC) senescence plays a negative role in pulmonary hypertension via juxtacrine interaction with smooth muscle cells (SMCs). By using EC-specific progeroid mice, we discovered that EC progeria deteriorated vascular remodeling in the lungs, and exacerbated pulmonary hypertension in mice. Mechanistically, senescent ECs overexpressed Notch ligands, which resulted in increased Notch signaling and activated proliferation and migration capacities in neighboring SMCs. Pharmacological inhibition of Notch signaling reduced the effects of senescent ECs on SMCs functions , and improved the worsened pulmonary hypertension in EC-specific progeroid mice . Our findings show that EC senescence is a critical disease-modifying factor in PAH and that EC-mediated Notch signaling is a pharmacotherapeutic target for the treatment of PAH, particularly in the elderly.
PubMed: 37192975
DOI: 10.1016/j.isci.2023.106662 -
Cells Apr 2023Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare human premature aging disorder that precipitates death because of cardiac disease. Almost all cases of HGPS...
Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare human premature aging disorder that precipitates death because of cardiac disease. Almost all cases of HGPS are caused by aberrant splicing of the gene that results in the production of a mutant Lamin A protein termed progerin. In our previous study, treatment with Progerinin has been shown to reduce progerin expression and improve aging phenotypes in vitro and in vivo HGPS models. In this record, cardiac parameters (stroke volume (SV), ejection fraction (EF), fractional shortening (FS), etc.) were acquired in and mice fed with either a vehicle diet or a Progerinin diet by echocardiography (from 38 weeks to 50 weeks at various ages), and then the cardiac function was analyzed. We also acquired the tissue samples and blood serum of and mice for pathological analysis at the end of echocardiography. From these data, we suggest that the administration of Progerinin in the HGPS model mouse can restore cardiac function and correct arterial abnormalities. These observations provide encouraging evidence for the efficacy of Progerinin for cardiac dysfunction in HGPS.
Topics: Mice; Humans; Animals; Progeria; Aging, Premature; Aging; Phenotype
PubMed: 37174632
DOI: 10.3390/cells12091232 -
BioRxiv : the Preprint Server For... Apr 2023Mutations to the gene cause laminopathies including Hutchinson-Gilford progeria syndrome (HGPS) that severely affect the cardiovascular system. The origins of tissue...
Mutations to the gene cause laminopathies including Hutchinson-Gilford progeria syndrome (HGPS) that severely affect the cardiovascular system. The origins of tissue specificity in these diseases are unclear, as the A-type Lamins are abundant and broadly expressed proteins. We show that A-type Lamin protein and transcript levels are uncorrelated across tissues. As protein-transcript discordance can be caused by variations in protein lifetime, we applied quantitative proteomics to profile protein turnover rates in healthy and progeroid tissues. We discover that tissue context and disease mutation each influence A-type Lamin protein lifetime. Lamin A/C has a weeks-long lifetime in the aorta, heart, and fat, where progeroid pathology is apparent, but a days-long lifetime in the liver and gastrointestinal tract, which are spared from disease. The A-type Lamins are insoluble and densely bundled in cardiovascular tissues, which may present an energetic barrier to degradation and promote long protein lifetime. Progerin is even more long-lived than Lamin A/C in the cardiovascular system and accumulates there over time. Progerin accumulation interferes broadly with protein homeostasis, as hundreds of abundant proteins turn over more slowly in progeroid tissues. These findings indicate that potential gene therapy interventions for HGPS will have significant latency and limited potency in disrupting the long-lived Progerin protein. Finally, we reveal that human disease alleles are significantly over-represented in the long-lived proteome, indicating that long protein lifetime may influence disease pathology and present a significant barrier to gene therapies for numerous human diseases.
PubMed: 37162946
DOI: 10.1101/2023.02.04.527139 -
Nature Aging Jun 2023
PubMed: 37130978
DOI: 10.1038/s43587-023-00427-9 -
Aging May 2023Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease....
Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry.
Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease. Fifty-one patients were enrolled and registered in the Werner Syndrome Registry. Their data were collected annually following registration. A cross-sectional analysis at registration and a longitudinal analysis between the baseline and each subsequent year was performed. Pearson's chi-squared and Wilcoxon signed-rank tests were used. Malignant neoplasms were observed from the fifth decade of life (mean onset: 49.7 years) and were observed in approximately 30% of patients during the 3-year survey period. Regarding renal function, the mean estimated glomerular filtration rate calculated from serum creatinine (eGFRcre) and eGFRcys, which were calculated from cystatin C in the first year, were 98.3 and 83.2 mL/min/1.73 m, respectively, and differed depending on the index used. In longitudinal analysis, the average eGFRcre for the first and fourth years was 74.8 and 63.4 mL/min/1.73 m, showing a rapid decline. Secular changes in Werner syndrome in multiple patients were identified. The prevalence of malignant neoplasms is high, and renal function may decline rapidly. It is, therefore, necessary to carry out active and detailed examinations and pay attention to the type and dose of the drugs used.
Topics: Humans; Kidney; Follow-Up Studies; Werner Syndrome; Cross-Sectional Studies; Sarcopenia; Cardiovascular Diseases; Kidney Diseases; Neoplasms; Creatinine
PubMed: 37130431
DOI: 10.18632/aging.204681