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Scientific Reports Oct 2023Alzheimer's Disease (AD) is a leading cause of dementia characterized by amyloid plaques and neurofibrillary tangles, and its pathogenesis remains unclear. Current...
Alzheimer's Disease (AD) is a leading cause of dementia characterized by amyloid plaques and neurofibrillary tangles, and its pathogenesis remains unclear. Current cellular models for AD often require several months to exhibit phenotypic features due to the lack of an aging environment in vitro. Lamin A is a key component of the nuclear lamina. Progerin, a truncated protein resulting from specific lamin A mutations, causes Hutchinson-Gilford Progeria Syndrome (HGPS), a disease that prematurely ages individuals. Studies have reported that lamin A expression is induced in the brains of AD patients, and overlapping cellular phenotypes have been observed between HGPS and AD cells. In this study, we investigated the effects of exogenous progerin expression on neural progenitor cells carrying familial AD mutations (FAD). Within three to four weeks of differentiation, these cells exhibited robust AD phenotypes, including increased tau phosphorylation, amyloid plaque accumulation, and an elevated Aβ42 to Aβ40 ratio. Additionally, progerin expression significantly increased AD cellular phenotypes such as cell death and cell cycle re-entry. Our results suggest that progerin expression could be used to create an accelerated model for AD development and drug screening.
Topics: Humans; Lamin Type A; Alzheimer Disease; Progeria; Aging; Cell Nucleus
PubMed: 37884611
DOI: 10.1038/s41598-023-45826-5 -
European Thyroid Journal Dec 2023Thyroid hormone signaling is essential for development, metabolism, and response to stress but declines during aging, the cause of which is unknown. DNA damage...
BACKGROUND
Thyroid hormone signaling is essential for development, metabolism, and response to stress but declines during aging, the cause of which is unknown. DNA damage accumulating with time is a main cause of aging, driving many age-related diseases. Previous studies in normal and premature aging mice, due to defective DNA repair, indicated reduced hepatic thyroid hormone signaling accompanied by decreased type 1 deiodinase (DIO1) and increased DIO3 activities. We investigated whether aging-related changes in deiodinase activity are driven by systemic signals or represent cell- or organ-autonomous changes.
METHODS
We quantified liver and plasma thyroid hormone concentrations, deiodinase activities and expression of T3-responsive genes in mice with a global, liver-specific and for comparison brain-specific inactivation of Xpg, one of the endonucleases critically involved in multiple DNA repair pathways.
RESULTS
Both in global and liver-specific Xpg knockout mice, hepatic DIO1 activity was decreased. Interestingly, hepatic DIO3 activity was increased in global, but not in liver-specific Xpg mutants. Selective Xpg deficiency and premature aging in the brain did not affect liver or systemic thyroid signaling. Concomitant with DIO1 inhibition, Xpg -/- and Alb-Xpg mice displayed reduced thyroid hormone-related gene expression changes, correlating with markers of liver damage and cellular senescence.
CONCLUSIONS
Our findings suggest that DIO1 activity during aging is predominantly modified in a tissue-autonomous manner driven by organ/cell-intrinsic accumulating DNA damage. The increase in hepatic DIO3 activity during aging largely depends on systemic signals, possibly reflecting the presence of circulating cells rather than activity in hepatocytes.
Topics: Animals; Mice; Aging; Aging, Premature; Brain; DNA Repair-Deficiency Disorders; Iodide Peroxidase; Liver; Mice, Knockout; Thyroid Hormones
PubMed: 37878415
DOI: 10.1530/ETJ-22-0231 -
Aging Cell Dec 2023Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal genetic condition that arises from a single nucleotide alteration in the LMNA gene, leading to the...
Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal genetic condition that arises from a single nucleotide alteration in the LMNA gene, leading to the production of a defective lamin A protein known as progerin. The accumulation of progerin accelerates the onset of a dramatic premature aging phenotype in children with HGPS, characterized by low body weight, lipodystrophy, metabolic dysfunction, skin, and musculoskeletal age-related dysfunctions. In most cases, these children die of age-related cardiovascular dysfunction by their early teenage years. The absence of effective treatments for HGPS underscores the critical need to explore novel safe therapeutic strategies. In this study, we show that treatment with the hormone ghrelin increases autophagy, decreases progerin levels, and alleviates other cellular hallmarks of premature aging in human HGPS fibroblasts. Additionally, using a HGPS mouse model (Lmna mice), we demonstrate that ghrelin administration effectively rescues molecular and histopathological progeroid features, prevents progressive weight loss in later stages, reverses the lipodystrophic phenotype, and extends lifespan of these short-lived mice. Therefore, our findings uncover the potential of modulating ghrelin signaling offers new treatment targets and translational approaches that may improve outcomes and enhance the quality of life for patients with HGPS and other age-related pathologies.
Topics: Adolescent; Child; Humans; Mice; Animals; Progeria; Aging, Premature; Ghrelin; Quality of Life; Skin; Lamin Type A; Aging
PubMed: 37858983
DOI: 10.1111/acel.13983 -
Mechanisms of Ageing and Development Dec 2023Hutchinson-Gilford progeria syndrome (HGPS), also known as hereditary progeria syndrome, is caused by mutations in the LMNA gene and the expression of progerin, which...
Hutchinson-Gilford progeria syndrome (HGPS), also known as hereditary progeria syndrome, is caused by mutations in the LMNA gene and the expression of progerin, which causes accelerated aging and premature death, with most patients dying of heart failure or other cardiovascular complications in their teens. HGPS patients are able to exhibit cardiovascular phenotypes similar to physiological aging, such as extensive atherosclerosis, smooth muscle cell loss, vascular lesions, and electrical and functional abnormalities of the heart. It also excludes the traditional risk causative factors of cardiovascular disease, making HGPS a new model for studying aging-related cardiovascular disease. Here, we analyzed the pathogenesis and pathophysiological characteristics of HGPS and the relationship between HGPS and cardiovascular disease, provided insight into the molecular mechanisms of cardiovascular disease pathogenesis in HGPS patients and treatment strategies for this disease. Moreover, we summarize the disease models used in HGPS studies to improve our understanding of the pathological mechanisms of cardiovascular aging in HGPS patients.
Topics: Humans; Adolescent; Progeria; Cardiovascular Diseases; Aging; Atherosclerosis; Cardiovascular System
PubMed: 37832833
DOI: 10.1016/j.mad.2023.111879 -
FEBS Letters Nov 2023Nuclear lamins are type-V intermediate filaments that are involved in many nuclear processes. In mammals, A- and B-type lamins assemble into separate physical meshwork... (Review)
Review
Nuclear lamins are type-V intermediate filaments that are involved in many nuclear processes. In mammals, A- and B-type lamins assemble into separate physical meshwork underneath the inner nuclear membrane, the nuclear lamina, with some residual fraction localized within the nucleoplasm. Lamins are the major part of the nucleoskeleton, providing mechanical strength and flexibility to protect the genome and allow nuclear deformability, while also contributing to gene regulation via interactions with chromatin. While lamins are the evolutionary ancestors of all intermediate filament family proteins, their ultimate filamentous assembly is markedly different from their cytoplasmic counterparts. Interestingly, hundreds of genetic mutations in the lamina proteins have been causally linked with a broad range of human pathologies, termed laminopathies. These include muscular, neurological and metabolic disorders, as well as premature aging diseases. Recent technological advances have contributed to resolving the filamentous structure of lamins and the corresponding lamina organization. In this review, we revisit the multiscale lamin organization and discuss its implications on nuclear mechanics and chromatin organization within lamina-associated domains.
Topics: Animals; Humans; Nuclear Lamina; Intermediate Filaments; Lamins; Cell Nucleus; Chromatin; Nuclear Envelope; Mammals
PubMed: 37813648
DOI: 10.1002/1873-3468.14750 -
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 -
GeroScience Apr 2024Progeroid syndromes such as Hutchinson Gilford Progeroid syndrome (HGPS), Werner syndrome (WS) and Cockayne syndrome (CS), result in severely reduced lifespans and...
Progeroid syndromes such as Hutchinson Gilford Progeroid syndrome (HGPS), Werner syndrome (WS) and Cockayne syndrome (CS), result in severely reduced lifespans and premature ageing. Normal senescent cells show splicing factor dysregulation, which has not yet been investigated in syndromic senescent cells. We sought to investigate the senescence characteristics and splicing factor expression profiles of progeroid dermal fibroblasts. Natural cellular senescence can be reversed by application of the senomorphic drug, trametinib, so we also investigated its ability to reverse senescence characteristics in syndromic cells. We found that progeroid cultures had a higher senescence burden, but did not always have differences in levels of proliferation, DNA damage repair and apoptosis. Splicing factor gene expression appeared dysregulated across the three syndromes. 10 µM trametinib reduced senescent cell load and affected other aspects of the senescence phenotype (including splicing factor expression) in HGPS and Cockayne syndromes. Werner syndrome cells did not demonstrate changes in in senescence following treatment. Splicing factor dysregulation in progeroid cells provides further evidence to support this mechanism as a hallmark of cellular ageing and highlights the use of progeroid syndrome cells in the research of ageing and age-related disease. This study suggests that senomorphic drugs such as trametinib could be a useful adjunct to therapy for progeroid diseases.
Topics: Humans; Werner Syndrome; Cockayne Syndrome; Alternative Splicing; Senotherapeutics; Progeria; RNA Splicing Factors; Pyridones; Pyrimidinones
PubMed: 37751047
DOI: 10.1007/s11357-023-00933-z -
Aging Cell Jan 2024Originally identified as an outcome of continuous culture of primary cells, cellular senescence has moved beyond the culture dish and is now a bona fide driver of aging... (Review)
Review
Originally identified as an outcome of continuous culture of primary cells, cellular senescence has moved beyond the culture dish and is now a bona fide driver of aging and disease in animal models, and growing links to human disease. This cellular stress response consists of a stable proliferative arrest coupled to multiple phenotypic changes. Perhaps the most important of these is the senescence-associated secretory phenotype, or senescence-associated secretory phenotype -a complex and variable collection of secreted molecules release by senescent cells with a number of potent biological activities. Senescent cells appear in multiple age-associated conditions in humans and mice, and interventions that eliminate these cells can prevent or even reverse multiple diseases in mouse models. Here, we review salient aspects of senescent cells in the context of human disease and homeostasis. Senescent cells increase in abundance during several diseases that associated with premature aging. Conversely, senescent cells have a key role in beneficial processes such as development and wound healing, and thus can help maintain tissue homeostasis. Finally, we speculate on mechanisms by which deleterious aspects of senescent cells might be targeted while retaining homeostatic aspects in order to improve age-related outcomes.
Topics: Humans; Animals; Mice; Aging; Cellular Senescence; Disease Models, Animal; Senescence-Associated Secretory Phenotype; Homeostasis
PubMed: 37731189
DOI: 10.1111/acel.13988 -
BMJ Case Reports Sep 2023
Topics: Humans; Progeria
PubMed: 37723091
DOI: 10.1136/bcr-2023-256203