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PeerJ 2023Aging is a natural and complex process characterized by the gradual deterioration of tissue and physiological functions in the organism over time. Cell senescence, a...
Aging is a natural and complex process characterized by the gradual deterioration of tissue and physiological functions in the organism over time. Cell senescence, a hallmark of aging, refers to the permanent and irreversible cell cycle arrest of proliferating cells triggered by endogenous stimuli or environmental stresses. Eliminating senescent cells has been shown to extend the healthy lifespan. In this study, we established a progeria mouse model with telomerase deficiency and confirmed the presence of shortened telomere length and increased expression of aging markers and in the organ tissues of G3 mice. We identified fisetin as a potent senolytic drug capable of reversing premature aging signs in telomerase-deficient mice. Fisetin treatment effectively suppressed the upregulation of aging markers and and reduced collagen fiber deposition. Furthermore, we observed a significant elevation in the mRNA level of in G3 mice, which was reduced after fisetin treatment. Stc1 has been implicated in anti-apoptotic processes through the upregulation of the Akt signaling pathway. Our findings reveal that fisetin exerts its anti-aging effect by inhibiting the Akt signaling pathway through the suppression of expression, leading to the apoptosis of senescent cells.
Topics: Animals; Mice; Telomerase; Cyclin-Dependent Kinase Inhibitor p16; Progeria; Proto-Oncogene Proteins c-akt; Telomere Shortening; Telomere; Aging
PubMed: 38107570
DOI: 10.7717/peerj.16463 -
Biology Feb 2024The primary cause of worldwide mortality and morbidity stems from complications in the cardiovascular system resulting from accelerated atherosclerosis and arterial... (Review)
Review
The primary cause of worldwide mortality and morbidity stems from complications in the cardiovascular system resulting from accelerated atherosclerosis and arterial stiffening. Frequently, both pathologies are associated with the pathological calcification of cardiovascular structures, present in areas such as cardiac valves or blood vessels (vascular calcification). The accumulation of hydroxyapatite, the predominant form of calcium phosphate crystals, is a distinctive feature of vascular calcification. This phenomenon is commonly observed as a result of aging and is also linked to various diseases such as diabetes, chronic kidney disease, and several genetic disorders. A substantial body of evidence indicates that vascular calcification involves two primary processes: a passive process and an active process. The physicochemical process of hydroxyapatite formation and deposition (a passive process) is influenced significantly by hyperphosphatemia. However, the active synthesis of calcification inhibitors, including proteins and low-molecular-weight inhibitors such as pyrophosphate, is crucial. Excessive calcification occurs when there is a loss of function in enzymes and transporters responsible for extracellular pyrophosphate metabolism. Current in vivo treatments to prevent calcification involve addressing hyperphosphatemia with phosphate binders and implementing strategies to enhance the availability of pyrophosphate.
PubMed: 38392329
DOI: 10.3390/biology13020111 -
GeroScience Feb 2024Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease caused by expression of progerin, a lamin A variant that is also expressed at low levels...
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease caused by expression of progerin, a lamin A variant that is also expressed at low levels in non-HGPS individuals. Although HGPS patients die predominantly from myocardial infarction and stroke, the mechanisms that provoke pathological alterations in the coronary and cerebral arteries in HGPS remain ill defined. Here, we assessed vascular function in the coronary arteries (CorAs) and carotid arteries (CarAs) of progerin-expressing Lmna mice (G609G), both in resting conditions and after hypoxic stimulus. Wire myography, pharmacological screening, and gene expression studies demonstrated vascular atony and stenosis, as well as other functional alterations in progeroid CorAs and CarAs and aorta. These defects were associated with loss of vascular smooth muscle cells and overexpression of the K7 family of voltage-dependent potassium channels. Compared with wild-type controls, G609G mice showed reduced median survival upon chronic isoproterenol exposure, a baseline state of chronic cardiac hypoxia characterized by overexpression of hypoxia-inducible factor 1α and 3α genes, and increased cardiac vascularization. Our results shed light on the mechanisms underlying progerin-induced coronary and carotid artery disease and identify K7 channels as a candidate target for the treatment of HGPS.
Topics: Humans; Mice; Animals; Progeria; Carotid Arteries; Hypoxia
PubMed: 37233881
DOI: 10.1007/s11357-023-00808-3 -
Clinical Genetics Dec 2023APOO/MIC26 is a subunit of the MICOS complex required for mitochondrial cristae morphology and function. Here, we report a novel variant of the APOO/MIC26 gene that...
APOO/MIC26 is a subunit of the MICOS complex required for mitochondrial cristae morphology and function. Here, we report a novel variant of the APOO/MIC26 gene that causes a severe mitochondrial disease with overall progeria-like phenotypes in two patients. Both patients developed partial agenesis of the corpus callosum, bilateral congenital cataract, hypothyroidism, and severe immune deficiencies. The patients died at an early age of 12 or 18 months. Exome sequencing revealed a mutation (NM_024122.5): c.532G>T (p.E178*) in the APOO/MIC26 gene that causes a nonsense mutation leading to the loss of 20 C-terminal amino acids. This mutation resulted in a highly unstable and degradation prone MIC26 protein, yet the remaining minute amounts of mutant MIC26 correctly localized to mitochondria and interacted physically with other MICOS subunits. MIC26 KO cells expressing MIC26 harboring the respective APOO/MIC26 mutation showed mitochondria with perturbed cristae architecture and fragmented morphology resembling MIC26 KO cells. We conclude that the novel mutation found in the APOO/MIC26 gene is a loss-of-function mutation impairing mitochondrial morphology and cristae morphogenesis.
Topics: Humans; Infant; Mitochondria; Mitochondrial Diseases; Mitochondrial Membranes; Mitochondrial Proteins; Phenotype; Progeria
PubMed: 37649161
DOI: 10.1111/cge.14420 -
Frontiers in Aging 2023According to current views the major hallmarks of physiological aging may be subdivided into three categories, primary causes of cellular damage (genomic instability,... (Review)
Review
According to current views the major hallmarks of physiological aging may be subdivided into three categories, primary causes of cellular damage (genomic instability, telomere attrition, loss of proteostasis, epigenetic alterations and compromised macroautophagy), antagonistic hallmarks that represent response to damage (deregulated nutrient sensing, cellular senescence, mitochondrial dysfunction) and integrative hallmarks that represent culprits of the phenotype (stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis). In contrast to physiological aging, premature aging diseases are driven by one or two distinct primary causes of aging, such as genomic instability in the case of Werner syndrome (WS), each displaying other hallmarks of aging to a variable extent. In this review we will focus on primary causes of well-investigated premature aging diseases Hutchinson-Gilford progeria syndrome (HGPS), WS, and Cockayne syndrome (CS) and for each provide an overview of reported aging hallmarks to elucidate resemblance to physiological aging on the mechanistic level and in the context of characteristic age-related diseases. Ubiquitous and tissue specific animal models of premature aging diseases will be discussed as useful tools to decipher fundamental aging-related mechanisms and develop intervention strategies to combat premature aging and age-related diseases.
PubMed: 38481648
DOI: 10.3389/fragi.2023.1327833 -
Aging Cell Feb 2024Several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether...
Several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether these models truly recapitulate natural aging. Here, we analyzed DNA methylation in multiple tissues of four previously reported mouse models of premature aging (Ercc1, LAKI, Polg, and Xpg). We estimated DNA methylation (DNAm) age of these samples using the Horvath clock. The most pronounced increase in DNAm age could be observed in Ercc1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair. Similarly, we detected an increase in epigenetic age in fibroblasts isolated from patients with progeroid syndromes associated with mutations in DNA excision repair genes. These findings highlight that mouse models with deficiencies in DNA repair, unlike other premature aging models, display accelerated epigenetic age, suggesting a strong connection between DNA damage and epigenetic dysregulation during aging.
Topics: Humans; Mice; Animals; Aging, Premature; Aging; DNA Repair; DNA Methylation; Proteins; Epigenesis, Genetic; DNA
PubMed: 38140713
DOI: 10.1111/acel.14058 -
Biomechanics and Modeling in... Aug 2023Hutchinson-Gilford Progeria Syndrome results in rapid aging and severe cardiovascular sequelae that accelerate near end-of-life. We found a progressive disease process...
Hutchinson-Gilford Progeria Syndrome results in rapid aging and severe cardiovascular sequelae that accelerate near end-of-life. We found a progressive disease process in proximal elastic arteries that was less evident in distal muscular arteries. Changes in aortic structure and function were then associated with changes in transcriptomics assessed via both bulk and single cell RNA sequencing, which suggested a novel sequence of progressive aortic disease: adverse extracellular matrix remodeling followed by mechanical stress-induced smooth muscle cell death, leading a subset of remnant smooth muscle cells to an osteochondrogenic phenotype that results in an accumulation of proteoglycans that thickens the aortic wall and increases pulse wave velocity, with late calcification exacerbating these effects. Increased central artery pulse wave velocity is known to drive left ventricular diastolic dysfunction, the primary diagnosis in progeria children. It appears that mechanical stresses above ~ 80 kPa initiate this progressive aortic disease process, explaining why elastic lamellar structures that are organized early in development under low wall stresses appear to be nearly normal whereas other medial constituents worsen progressively in adulthood. Mitigating early mechanical stress-driven smooth muscle cell loss/phenotypic modulation promises to have important cardiovascular implications in progeria patients.
Topics: Child; Humans; Progeria; Pulse Wave Analysis; Phenotype; Aortic Diseases; Myocytes, Smooth Muscle
PubMed: 37149823
DOI: 10.1007/s10237-023-01722-5 -
International Journal of Molecular... Feb 2024Ferroptosis, a unique form of programmed cell death trigged by lipid peroxidation and iron accumulation, has been implicated in embryonic erythropoiesis and aging. Our...
Ferroptosis, a unique form of programmed cell death trigged by lipid peroxidation and iron accumulation, has been implicated in embryonic erythropoiesis and aging. Our previous research demonstrated that lysophosphatidic acid receptor 3 (LPA) activation mitigated oxidative stress in progeria cells and accelerated the recovery of acute anemia in mice. Given that both processes involve iron metabolism, we hypothesized that LPA activation might mediate cellular ferroptosis. In this study, we used an LPA agonist, 1-Oleoyl-2-O-methyl-rac-glycerophosphothionate (OMPT), to activate LPA and examine its effects on the ferroptosis process. OMPT treatment elevated anti-ferroptosis gene protein expression, including solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), heme oxygenase-1 (HO-1), and ferritin heavy chain (FTH1), in erastin-induced cells. Furthermore, OMPT reduced lipid peroxidation and intracellular ferrous iron accumulation, as evidenced by C11 BODIPY™ 581/591 Lipid Peroxidation Sensor and FerroOrange staining. These observations were validated by applying siRNA in the experiments mentioned above. In addition, the protein expression level of nuclear factor erythroid 2-related factor (NRF2), a key regulator of oxidative stress, was also enhanced in OMPT-treated cells. Lastly, we verified that LPA plays a critical role in erastin-induced ferroptotic human erythroleukemia K562 cells. OMPT rescued the erythropoiesis defect caused by erastin in K562 cells based on a promoter luciferase assay. Taken together, our findings suggest that LPA activation inhibits cell ferroptosis by suppressing lipid oxidation and iron accumulation, indicating that ferroptosis could potentially serve as a link among LPA, erythropoiesis, and aging.
Topics: Mice; Animals; Humans; Receptors, Lysophosphatidic Acid; Ferroptosis; Apoptosis; Oxidative Stress; NF-E2-Related Factor 2; Iron
PubMed: 38397002
DOI: 10.3390/ijms25042315 -
Long lifetime and tissue-specific accumulation of lamin A/C in Hutchinson-Gilford progeria syndrome.The Journal of Cell Biology Jan 2024LMNA mutations cause laminopathies that afflict the cardiovascular system and include Hutchinson-Gilford progeria syndrome. The origins of tissue specificity in these...
LMNA mutations cause laminopathies that afflict the cardiovascular system and include Hutchinson-Gilford progeria syndrome. The origins of tissue specificity in these diseases are unclear as the lamin A/C proteins are broadly expressed. We show that LMNA transcript levels are not predictive of lamin A/C protein levels across tissues and use quantitative proteomics to discover that tissue context and disease mutation each influence lamin A/C protein's lifetime. Lamin A/C's lifetime is an order of magnitude longer in the aorta, heart, and fat, where laminopathy pathology is apparent, than in the liver and intestine, which are spared from the disease. Lamin A/C is especially insoluble in cardiovascular tissues, which may limit degradation and promote protein stability. Progerin is even more long lived than lamin A/C in the cardiovascular system and accumulates there over time. Progerin accumulation is associated with impaired turnover of hundreds of abundant proteins in progeroid tissues. These findings identify impaired lamin A/C protein turnover as a novel feature of laminopathy syndromes.
Topics: Humans; Lamin Type A; Mutation; Progeria; Proteomics
PubMed: 37966721
DOI: 10.1083/jcb.202307049 -
Biological Reviews of the Cambridge... Aug 2023The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing...
The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. Although controversial, this is supported by firm evidence that semelparous species display evolutionarily programmed ageing in response to reproductive and environmental cues. Parabiosis experiments reveal that ageing is orchestrated systemically through the circulation, accompanied by programmed changes in hormone levels across a lifetime. This implies that, like the circadian and circannual clocks, there is a master 'clock of age' (circavital clock) located in the limbic brain of mammals that modulates systemic changes in growth factor and hormone secretion over the lifespan, as well as systemic alterations in gene expression as revealed by genomic methylation analysis. Studies on accelerated ageing in mice, as well as human longevity genes, converge on evolutionarily conserved fibroblast growth factors (FGFs) and their receptors, including KLOTHO, as well as insulin-like growth factors (IGFs) and steroid hormones, as key players mediating the systemic effects of ageing. Age-related changes in these and multiple other factors are inferred to cause a progressive decline in tissue maintenance through failure of stem cell replenishment. This most severely affects the immune system, which requires constant renewal from bone marrow stem cells. Age-related immune decline increases risk of infection whereas lifespan can be extended in germfree animals. This and other evidence suggests that infection is the major cause of death in higher organisms. Immune decline is also associated with age-related diseases. Taking the example of Alzheimer's disease (AD), we assess the evidence that AD is caused by immunosenescence and infection. The signature protein of AD brain, Aβ, is now known to be an antimicrobial peptide, and Aβ deposits in AD brain may be a response to infection rather than a cause of disease. Because some cognitively normal elderly individuals show extensive neuropathology, we argue that the location of the pathology is crucial - specifically, lesions to limbic brain are likely to accentuate immunosenescence, and could thus underlie a vicious cycle of accelerated immune decline and microbial proliferation that culminates in AD. This general model may extend to other age-related diseases, and we propose a general paradigm of organismal senescence in which declining stem cell proliferation leads to programmed immunosenescence and mortality.
Topics: Animals; Humans; Mice; Aged; Immunosenescence; Alzheimer Disease; Cell Self Renewal; Aging; Mammals; Hormones
PubMed: 37068798
DOI: 10.1111/brv.12959