-
Aging Cell Dec 2023The NAD -dependent deacylase family of sirtuin enzymes have been implicated in biological ageing, late-life health and overall lifespan, though of these members, a role...
The NAD -dependent deacylase family of sirtuin enzymes have been implicated in biological ageing, late-life health and overall lifespan, though of these members, a role for sirtuin-2 (SIRT2) is less clear. Transgenic overexpression of SIRT2 in the BubR1 hypomorph model of progeria can rescue many aspects of health and increase overall lifespan, due to a specific interaction between SIRT2 and BubR1 that improves the stability of this protein. It is less clear whether SIRT2 is relevant to biological ageing outside of a model where BubR1 is under-expressed. Here, we sought to test whether SIRT2 over-expression would impact the overall health and lifespan of mice on a nonprogeroid, wild-type background. While we previously found that SIRT2 transgenic overexpression prolonged female fertility, here, we did not observe any additional impact on health or lifespan, which was measured in both male and female mice on standard chow diets, and in males challenged with a high-fat diet. At the biochemical level, NMR studies revealed an increase in total levels of a number of metabolites in the brain of SIRT2-Tg animals, pointing to a potential impact in cell composition; however, this did not translate into functional differences. Overall, we conclude that strategies to enhance SIRT2 protein levels may not lead to increased longevity.
Topics: Animals; Female; Male; Mice; Aging; Animals, Genetically Modified; Brain; Longevity; Sirtuin 2
PubMed: 38009412
DOI: 10.1111/acel.14027 -
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 -
Frontiers in Cell and Developmental... 2023Despite being among the most intensively studied oncogenes, its role in normal development has not been determined as mice do not survival beyond mid-gestation. ±... (Review)
Review
Despite being among the most intensively studied oncogenes, its role in normal development has not been determined as mice do not survival beyond mid-gestation. ± mice live longer than their wild-type counterparts and are slower to accumulate many age-related phenotypes. However, haplo-insufficiency likely conceals other important phenotypes as many high-affinity Myc targets genes continue to be regulated normally. By delaying inactivation until after birth it has recently been possible to study the consequences of its near-complete total body loss and thus to infer its normal function. Against expectation, these KO" mice lived significantly longer than control wild-type mice but manifested a marked premature aging phenotype. This seemingly paradoxical behavior was potentially explained by a >3-fold lower lifetime incidence of cancer, normally the most common cause of death in mice and often Myc-driven. loss accelerated the accumulation of numerous "Aging Hallmarks", including the loss of mitochondrial and ribosomal structural and functional integrity, the generation of reactive oxygen species, the acquisition of genotoxic damage, the detrimental rewiring of metabolism and the onset of senescence. In both mice and humans, normal aging in many tissues was accompaniued by the downregulation of Myc and the loss of Myc target gene regulation. Unlike most mouse models of premature aging, which are based on monogenic disorders of DNA damage recognition and repair, the KO mouse model directly impacts most Aging Hallmarks and may therefore more faithfully replicate the normal aging process of both mice and humans. It further establishes that the strong association between aging and cancer can be genetically separated and is maintained by a single gene.
PubMed: 37621775
DOI: 10.3389/fcell.2023.1244321 -
Aging Cell Oct 2023Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by nuclear envelope alterations that lead to accelerated aging and premature death. Several...
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by nuclear envelope alterations that lead to accelerated aging and premature death. Several studies have linked health and longevity to cell-extrinsic mechanisms, highlighting the relevance of circulating factors in the aging process as well as in age-related diseases. We performed a global plasma proteomic analysis in two preclinical progeroid models (Lmna and Zmpste24 mice) using aptamer-based proteomic technology. Pathways related to the extracellular matrix, growth factor response and calcium ion binding were among the most enriched in the proteomic signature of progeroid samples compared to controls. Despite the global downregulation trend found in the plasma proteome of progeroid mice, several proteins associated with cardiovascular disease, the main cause of death in HGPS, were upregulated. We also developed a chronological age predictor using plasma proteome data from a cohort of healthy mice (aged 1-30 months), that reported an age acceleration when applied to progeroid mice, indicating that these mice exhibit an "old" plasma proteomic signature. Furthermore, when compared to naturally-aged mice, a great proportion of differentially expressed circulating proteins in progeroid mice were specific to premature aging, highlighting secretome-associated differences between physiological and accelerated aging. This is the first large-scale profiling of the plasma proteome in progeroid mice, which provides an extensive list of candidate circulating plasma proteins as potential biomarkers and/or therapeutic targets for further exploration and hypothesis generation in the context of both physiological and premature aging.
Topics: Humans; Mice; Animals; Progeria; Aging, Premature; Proteomics; Proteome; Secretome; Lamin Type A
PubMed: 37565451
DOI: 10.1111/acel.13952 -
Aging Mar 2020
Topics: Aging; Humans; Karyopherins; Nuclear Proteins; Progeria; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Exportin 1 Protein
PubMed: 32200356
DOI: 10.18632/aging.102948 -
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 -
Cells Aug 2020Laminopathies are rare and heterogeneous diseases affecting one to almost all tissues, as in Progeria, and sharing certain features such as metabolic disorders and a... (Review)
Review
Laminopathies are rare and heterogeneous diseases affecting one to almost all tissues, as in Progeria, and sharing certain features such as metabolic disorders and a predisposition to atherosclerotic cardiovascular diseases. These two features are the main characteristics of the adipose tissue-specific laminopathy called familial partial lipodystrophy type 2 (FPLD2). The only gene that is involved in FPLD2 physiopathology is the gene, with at least 20 mutations that are considered pathogenic. encodes the type V intermediate filament lamin A/C, which is incorporated into the lamina meshwork lining the inner membrane of the nuclear envelope. Lamin A/C is involved in the regulation of cellular mechanical properties through the control of nuclear rigidity and deformability, gene modulation and chromatin organization. While recent studies have described new potential signaling pathways dependent on lamin A/C and associated with FPLD2 physiopathology, the whole picture of how the syndrome develops remains unknown. In this review, we summarize the signaling pathways involving lamin A/C that are associated with the progression of FPLD2. We also explore the links between alterations of the cellular mechanical properties and FPLD2 physiopathology. Finally, we introduce potential tools based on the exploration of cellular mechanical properties that could be redirected for FPLD2 diagnosis.
Topics: Adipocytes; Endothelial Cells; Humans; Lipodystrophy, Familial Partial; Signal Transduction
PubMed: 32842478
DOI: 10.3390/cells9091947 -
Cells Sep 2023Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by the mutant protein progerin, which is expressed by the abnormal splicing of... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by the mutant protein progerin, which is expressed by the abnormal splicing of the gene. HGPS affects systemic levels, with the exception of cognition or brain development, in children, showing that cellular aging can occur in the short term. Studying progeria could be useful in unraveling the causes of human aging (as well as fatal age-related disorders). Elucidating the clear cause of HGPS or the development of a therapeutic medicine could improve the quality of life and extend the survival of patients. This review aimed to (i) briefly describe how progerin was discovered as the causative agent of HGPS, (ii) elucidate the puzzling observation of the absence of primary neurological disease in HGPS, (iii) present several studies showing the deleterious effects of progerin and the beneficial effects of its inhibition, and (iv) summarize research to develop a therapy for HGPS and introduce clinical trials for its treatment.
Topics: Child; Humans; Lamin Type A; Progeria; Quality of Life; Medicine; Aging; Rare Diseases
PubMed: 37759521
DOI: 10.3390/cells12182299 -
Nucleic Acids Research Sep 2022Mutations in the lamin A/C gene (LMNA) cause laminopathies such as the premature aging Hutchinson Gilford progeria syndrome (HGPS) and altered lamin A/C levels are found...
Mutations in the lamin A/C gene (LMNA) cause laminopathies such as the premature aging Hutchinson Gilford progeria syndrome (HGPS) and altered lamin A/C levels are found in diverse malignancies. The underlying lamin-associated mechanisms remain poorly understood. Here we report that lamin A/C-null mouse embryo fibroblasts (Lmna-/- MEFs) and human progerin-expressing HGPS fibroblasts both display reduced NAD+ levels, unstable mitochondrial DNA and attenuated bioenergetics. This mitochondrial dysfunction is associated with reduced chromatin recruitment (Lmna-/- MEFs) or low levels (HGPS) of PGC1α, the key transcription factor for mitochondrial homeostasis. Lmna-/- MEFs showed reduced expression of the NAD+-biosynthesis enzyme NAMPT and attenuated activity of the NAD+-dependent deacetylase SIRT1. We find high PARylation in lamin A/C-aberrant cells, further decreasing the NAD+ pool and consistent with impaired DNA base excision repair in both cell models, a condition that fuels DNA damage-induced PARylation under oxidative stress. Further, ATAC-sequencing revealed a substantially altered chromatin landscape in Lmna-/- MEFs, including aberrantly reduced accessibility at the Nampt gene promoter. Thus, we identified a new role of lamin A/C as a key modulator of mitochondrial function through impairments of PGC1α and the NAMPT-NAD+ pathway, with broader implications for the aging process.
Topics: Animals; Chromatin; DNA, Mitochondrial; Fibroblasts; Humans; Lamin Type A; Mice; Mitochondria; NAD; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Progeria; Sirtuin 1
PubMed: 36099415
DOI: 10.1093/nar/gkac741 -
Nutrients May 2021A series of problems including osteopathy, abnormal serum data, and vascular calcification associated with chronic kidney disease (CKD) are now collectively called... (Review)
Review
A series of problems including osteopathy, abnormal serum data, and vascular calcification associated with chronic kidney disease (CKD) are now collectively called CKD-mineral bone disease (CKD-MBD). The pathophysiology of CKD-MBD is becoming clear with the emerging of αKlotho, originally identified as a progeria-causing protein, and bone-derived phosphaturic fibroblast growth factor 23 (FGF23) as associated factors. Meanwhile, compared with calcium and parathyroid hormone, which have long been linked with CKD-MBD, phosphate is now attracting more attention because of its association with complications and outcomes. Incidentally, as the pivotal roles of FGF23 and αKlotho in phosphate metabolism have been unveiled, how phosphate metabolism and hyperphosphatemia are involved in CKD-MBD and how they can be clinically treated have become of great interest. Thus, the aim of this review is reconsider CKD-MBD from the viewpoint of phosphorus, its involvement in the pathophysiology, causing complications, therapeutic approach based on the clinical evidence, and clarifying the importance of phosphorus management.
Topics: Aging; Animals; Bone and Bones; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperphosphatemia; Klotho Proteins; Membrane Proteins; Parathyroid Hormone; Phosphates; Phosphorus; Renal Insufficiency, Chronic; Risk Factors; Vascular Calcification
PubMed: 34069053
DOI: 10.3390/nu13051670