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Aging Oct 2020
Topics: Aging; Animals; Humans; Magnesium; Models, Biological; Oxidation-Reduction; Oxidative Stress; Progeria
PubMed: 33173016
DOI: 10.18632/aging.104211 -
Cells Feb 2020Hutchinson-Gilford Progeria Syndrome (HGPS) is a segmental premature aging disease causing patient death by early teenage years from cardiovascular dysfunction. Although... (Review)
Review
Hutchinson-Gilford Progeria Syndrome (HGPS) is a segmental premature aging disease causing patient death by early teenage years from cardiovascular dysfunction. Although HGPS does not totally recapitulate normal aging, it does harbor many similarities to the normal aging process, with patients also developing cardiovascular disease, alopecia, bone and joint abnormalities, and adipose changes. It is unsurprising, then, that as physicians and scientists have searched for treatments for HGPS, they have targeted many pathways known to be involved in normal aging, including inflammation, DNA damage, epigenetic changes, and stem cell exhaustion. Although less studied at a mechanistic level, severe metabolic problems are observed in HGPS patients. Interestingly, new research in animal models of HGPS has demonstrated impressive lifespan improvements secondary to metabolic interventions. As such, further understanding metabolism, its contribution to HGPS, and its therapeutic potential has far-reaching ramifications for this disease still lacking a robust treatment strategy.
Topics: Animals; Disease Models, Animal; Energy Metabolism; Humans; Progeria
PubMed: 32046343
DOI: 10.3390/cells9020395 -
Aging Apr 2021
Topics: Aging; Cellular Senescence; CpG Islands; DNA Methylation; Epigenesis, Genetic; Genomic Instability; Humans; Interferon Type I; Progeria; Repetitive Sequences, Nucleic Acid; Signal Transduction
PubMed: 33895726
DOI: 10.18632/aging.203020 -
Circulation Research Apr 2023The pathophysiology of vascular disease is linked to accelerated biological aging and a combination of genetic, lifestyle, biological, and environmental risk factors.... (Review)
Review
The pathophysiology of vascular disease is linked to accelerated biological aging and a combination of genetic, lifestyle, biological, and environmental risk factors. Within the scenario of uncontrolled artery wall aging processes, CKD (chronic kidney disease) stands out as a valid model for detailed structural, functional, and molecular studies of this process. The cardiorenal syndrome relates to the detrimental bidirectional interplay between the kidney and the cardiovascular system. In addition to established risk factors, this group of patients is subjected to a plethora of other emerging vascular risk factors, such as inflammation, oxidative stress, mitochondrial dysfunction, vitamin K deficiency, cellular senescence, somatic mutations, epigenetic modifications, and increased apoptosis. A better understanding of the molecular mechanisms through which the uremic milieu triggers and maintains early vascular aging processes, has provided important new clues on inflammatory pathways and emerging risk factors alike, and to the altered behavior of cells in the arterial wall. Advances in the understanding of the biology of uremic early vascular aging opens avenues to novel pharmacological and nutritional therapeutic interventions. Such strategies hold promise to improve future prevention and treatment of early vascular aging not only in CKD but also in the elderly general population.
Topics: Humans; Aged; Renal Insufficiency, Chronic; Aging; Vascular Diseases; Kidney; Cellular Senescence
PubMed: 37053277
DOI: 10.1161/CIRCRESAHA.122.321751 -
Aging Cell Apr 2024Beyond the antimicrobial activity, doxycycline (DOX) exhibits longevity-promoting effect in nematodes, while its effect on mammals is unclear. Here, we applied a mouse...
Beyond the antimicrobial activity, doxycycline (DOX) exhibits longevity-promoting effect in nematodes, while its effect on mammals is unclear. Here, we applied a mouse model of Hutchinson-Gilford progeria syndrome (HGPS), Zmpste24 knockout (KO) mice, and analyzed the antiaging effect of DOX. We found that the DOX treatment prolongs lifespan and ameliorates progeroid features of Zmpste24 KO mice, including the decline of body and tissue weight, exercise capacity and cortical bone density, and the shortened colon length. DOX treatment alleviates the abnormal nuclear envelope in multiple tissues, and attenuates cellular senescence and cell death of Zmpste24 KO and HGPS fibroblasts. DOX downregulates the level of proinflammatory IL6 in both serum and tissues. Moreover, the elevated α-tubulin (K40) acetylation mediated by NAT10 in progeria, is rescued by DOX treatment in the aorta tissues in Zmpste24 KO mice and fibroblasts. Collectively, our study uncovers that DOX can decelerate aging in progeria mice via counteracting IL6 expression and NAT10-mediated acetylation of α-tubulin.
PubMed: 38686927
DOI: 10.1111/acel.14188 -
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 -
The Journal of Cell Biology Jan 2024Mutations in genes encoding nuclear lamins cause diseases called laminopathies. In this issue, Hasper et al. (https://doi.org/10.1083/jcb.202307049) show that lamin A/C...
Mutations in genes encoding nuclear lamins cause diseases called laminopathies. In this issue, Hasper et al. (https://doi.org/10.1083/jcb.202307049) show that lamin A/C and the prelamin A variant in Hutchinson-Gilford progeria syndrome have relatively long lifetimes in affected tissues.
Topics: Humans; Lamins; Lamin Type A; Nuclear Lamina; Progeria
PubMed: 38078930
DOI: 10.1083/jcb.202311193 -
Bone Oct 2021The nuclear envelope and nucleoskeleton are emerging as signaling centers that regulate how physical information from the extracellular matrix is biochemically... (Review)
Review
The nuclear envelope and nucleoskeleton are emerging as signaling centers that regulate how physical information from the extracellular matrix is biochemically transduced into the nucleus, affecting chromatin and controlling cell function. Bone is a mechanically driven tissue that relies on physical information to maintain its physiological function and structure. Disorder that present with musculoskeletal and cardiac symptoms, such as Emery-Dreifuss muscular dystrophies and progeria, correlate with mutations in nuclear envelope proteins including Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, Lamin A/C, and emerin. However, the role of nuclear envelope mechanobiology on bone function remains underexplored. The mesenchymal stem cell (MSC) model is perhaps the most studied relationship between bone regulation and nuclear envelope function. MSCs maintain the musculoskeletal system by differentiating into multiple cell types including osteocytes and adipocytes, thus supporting the bone's ability to respond to mechanical challenge. In this review, we will focus on how MSC function is regulated by mechanical challenges both in vitro and in vivo within the context of bone function specifically focusing on integrin, β-catenin and YAP/TAZ signaling. The importance of the nuclear envelope will be explored within the context of musculoskeletal diseases related to nuclear envelope protein mutations and nuclear envelope regulation of signaling pathways relevant to bone mechanobiology in vitro and in vivo.
Topics: Biophysics; Cell Nucleus; Cytoskeleton; Humans; Muscular Dystrophy, Emery-Dreifuss; Nuclear Envelope
PubMed: 34051417
DOI: 10.1016/j.bone.2021.116023 -
Annual Review of Cell and Developmental... Oct 2021The cell nucleus is best known as the container of the genome. Its envelope provides a barrier for passive macromolecule diffusion, which enhances the control of gene... (Review)
Review
The cell nucleus is best known as the container of the genome. Its envelope provides a barrier for passive macromolecule diffusion, which enhances the control of gene expression. As its largest and stiffest organelle, the nucleus also defines the minimal space requirements of a cell. Internal or external pressures that deform a cell to its physical limits cause a corresponding nuclear deformation. Evidence is consolidating that the nucleus, in addition to its genetic functions, serves as a physical sensing device for critical cell body deformation. Nuclear mechanotransduction allows cells to adapt their acute behaviors, mechanical stability, paracrine signaling, and fate to their physical surroundings. This review summarizes the basic chemical and mechanical properties of nuclear components, and how these properties are thought to be utilized for mechanosensing.
Topics: Cell Nucleus; Mechanotransduction, Cellular
PubMed: 34213953
DOI: 10.1146/annurev-cellbio-120319-030049 -
Molecular Medicine (Cambridge, Mass.) Jul 2023The telomerase RNA component (TERC) gene plays an important role in telomerase-dependent extension and maintenance of the telomeres. In the event of TERC... (Review)
Review
The telomerase RNA component (TERC) gene plays an important role in telomerase-dependent extension and maintenance of the telomeres. In the event of TERC haploinsufficiency, telomere length is often affected; this, in turn, can result in the development of progeria-related diseases such as aplastic anemia (AA) and congenital keratosis. Cell reprogramming can reverse the differentiation process and can, therefore, transform cells into pluripotent stem cells with stronger differentiation and self-renewal abilities; further, cell reprograming can also extend the telomere length of these cells, which may be crucial in the diagnosis and treatment of telomere depletion diseases such as AA. In this study, we summarized the effects of TERC haploid cell reprogramming on telomere length and the correlation between this alteration and the pathogenesis of AA; by investigating the role of cell reprogramming in AA, we aimed to identify novel diagnostic indicators and therapeutic strategies for patients with AA.
Topics: Humans; Telomerase; Anemia, Aplastic; Cellular Reprogramming; Haploidy
PubMed: 37424004
DOI: 10.1186/s10020-023-00691-w