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At least 685 records · Page 38Linked to original sources
PubMed2003

Age-related trends in gene expression in the chemosensory-nasal mucosae of senescence-accelerated mice.

We have utilized high-density GeneChip oligonucleotide arrays to investigate the use of the senescence-accelerated mouse (SAM) as a biogerontological resource to identify patterns of gene expression in the chemosensory-nasal mucosa. Gene profiling in chronologically young and old mice of the senescence-resistant (SAMR) and senescence-prone (SAMP) strains revealed 133 known genes that were modulated by a three-fold or greater change either in one strain or the other or in both strains during aging. We also identified known genes in our study which based on their encoded proteins were identified as aging-related genes in the aging neocortex and cerebellum of mice as reported by Lee et al. (2000) [Nat. Genet. 25 (2000) 294]. Changes in gene profiles for chemosensory-related genes including olfactory and vomeronasal receptors, sensory transduction-associated proteins, and odor and pheromone transport molecules in the young SAMR and SAMP were compared with age-matched C57BL/6J mice. An analysis of known gene expression profiles suggests that changes in the expression of immune factor genes and genes associated with cell cycle progression and cell death were particularly prominent in the old SAM strains. A preliminary cellular validation study supported the dysregulation of cell cycle-related genes in the old SAM strains. The results of our initial study indicated that the use of the SAM models of aging could provide substantive information leading to a more fundamental understanding of the aging process in the chemosensory-nasal mucosa at the genomic, molecular, and cellular levels.

Aging↗
PubMed2006

A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.

XPF-ERCC1 endonuclease is required for repair of helix-distorting DNA lesions and cytotoxic DNA interstrand crosslinks. Mild mutations in XPF cause the cancer-prone syndrome xeroderma pigmentosum. A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms. It is not known how unrepaired DNA damage accelerates ageing or its relevance to natural ageing. Here we show a highly significant correlation between the liver transcriptome of old mice and a mouse model of this progeroid syndrome. Expression data from XPF-ERCC1-deficient mice indicate increased cell death and anti-oxidant defences, a shift towards anabolism and reduced growth hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of lifespan. Similar changes are seen in wild-type mice in response to chronic genotoxic stress, caloric restriction, or with ageing. We conclude that unrepaired cytotoxic DNA damage induces a highly conserved metabolic response mediated by the IGF1/insulin pathway, which re-allocates resources from growth to somatic preservation and life extension. This highlights a causal contribution of DNA damage to ageing and demonstrates that ageing and end-of-life fitness are determined both by stochastic damage, which is the cause of functional decline, and genetics, which determines the rates of damage accumulation and decline.

Aging↗
PubMed2004

Maintaining integrity.

Research on genome stability and integrity now extends far beyond the biochemistry of DNA repair to encompass signal transduction pathways that span numerous aspects of cellular life. Derailed genomic integrity pathways can result in debilitating genetic disorders, premature ageing, predisposition to cancer and degenerative conditions. Current progress in this rapidly expanding field was the subject of an EMBO workshop, Maintenance of Genomic Integrity, that took place in June 2004 in Galway, Ireland. Top

Animals↗
PubMed2026

CK2α restriction of STING accumulation underlies systemic aging.

Chronic activation of the cGAS-STING pathway drives inflammaging and cellular senescence. Although nuclear envelope (NE) barrier failure leading to cytoplasmic chromatin leakage is a key trigger, the molecular mechanisms governing STING activity at the NE during aging remain poorly understood. Here, we identify lamin A/C (LMNA) as a critical NE scaffold that orchestrates STING regulation by recruiting both STING and Casein Kinase 2 (CK2α). We demonstrate that LMNA facilitates the phosphorylation of STING at Ser366 by CK2α, which promotes STING turnover and restricts its accumulation, thereby attenuating pathway activation and mitigating senescence in myeloid cells as well as systemic aging. Strikingly, pharmacologic STING inhibition in vivo robustly rescues progeroid phenotypes-including loss of bone density and multi-tissue senescence-and extends lifespan in progeroid mouse models. Moreover, H-151 treatment also ameliorates the premature aging phenotypes induced by myeloid-specific CK2α ablation. In contrast, constitutive STING ablation yields limited survival benefits, revealing that controlled attenuation of STING signaling, rather than complete elimination, drives therapeutic efficacy. Our findings establish the LMNA-CK2-STING axis as a key biochemical mechanism that suppresses innate immune activation at the NE, offering a promising strategy for ameliorating aging and progeroid pathologies.

Animals↗
PubMedDate not supplied

[Neonatal progeroid syndrome (Wiedemann-Rautenstrauch syndrome): case report and review of the literature].

The neonatal progeroid syndrome represents a complex of symptoms with unknown cause and pathogenesis. At 37 weeks of uncomplicated pregnancy a boy of non-consanguineous turkish parents was delivered by section. The weight of 1740 g and the length of 43 cm were striking, the circumference of the head was still within normal range. Further on the patient showed the diagnostic criteria of Wiedemann-Rautenstrauch syndrome: Beside growth failure and nearly absence of subcutaneous fat, old-looking face with hydrocephalic appearance, prominent scalp veins and sparse scalp hair, large hands and feet with long fingers and toes were found. Neonatal teeth didn't exist. But neonatal teeth are not always present in this syndrome. Among 19 published cases they were also not described in 6 cases (31.6%). Cataract was not found. A skin biopsy taken at the age of four months revealed an extremely thin dermis with pronounced rarefication of elastic material by light microscopy. On the electron microscopical level, no qualitative morphological aberrations or signs of degeneration were found, but normal although very small elastic fibres. With increasing age the appearance was nearly unchanged. In spite of high-caloric nutrition the increase of weight was not sufficient. The clinical symptoms of this patients were compared with the 19 already published cases of Wiedemann-Rautenstrauch syndrome. This shall be a contribution to the exact description of that extremely rare syndrome. We hope to facilitate, that hereby the differential diagnosis in difficult cases will be more easy. Because of heterogeneity it has to discuss if the Wiedemann-Rautenstrauch syndrome really represents a separate genetic entity within the group of premature aging syndromes.

Biopsy↗
PubMedDate not supplied

[Kyphoscoliosis in Wiedemann-Rautenstrauch-syndrome (neonatal progeroid syndrome)].

AIM: The Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome, WR syndrome) is a rare autosomal recessive disorder including premature aging already at birth. Most of the patients show an aged face, a craniofacial dysmorphism, decreased subcutaneous fat tissue, a significant developmental delay, and have a short life expectation. We present the second patient described in literature reaching an age of 16 years. Furthermore this patient developed a progressive scoliosis during childhood which to our knowledge has not been reported before among individuals affected by Wiedemann-Rautenstrauch syndrome. The pathogenetic features of the spinal deformity are discussed and the operative management is described. METHOD: The patient underwent a three-stage correction of her spinal deformity (anterior thoracic and lumbar release and posterior release, correction of the deformity with instrumentation and fusion) supported by Halo traction and physiotherapy. RESULTS: At the latest follow-up 12 months postoperatively the patient showed a stable correction from 78 degrees to 38 degrees in the frontal plane with physiologic sagittal alignment both clinically and radiologically. CONCLUSION: The scoliosis of our patient with Wiedemann-Rautenstrauch syndrome showed radiologically and clinically the characteristics of a neuromuscular curve. Since the curve showed a significant progression and high rigidity operative correction and fusion was indicated. We recommend a staged operative management to minimize the high risks of the operations and possible complications from cardiological and respiratory dysfunction associated with WR syndrome.

Adolescent↗
PubMed2005

Reduced phosphorylation of transcription factor Elk-1 in cultured fibroblasts of a patient with premature aging syndrome and insulin resistance.

The effect of insulin and growth factor mediated signaling to gene regulation was investigated in cultured fibroblasts of a patient with a premature aging syndrome (metageria) and severe insulin resistance. Insulin receptor structure and function as well as major pathways activated by insulin, i.e. phosphatidyl inositol-3 kinase (PI-3 K) cascade or mitogen-activated protein kinase (MAPK) cascades, were functional. Inducibility of the proto-oncogene cfos, a representative endpoint of signaling pathways related to gene expression, by growth factors or insulin was reduced in patient cells. This reduced induction persisted in cfos promoter reporter gene studies indicating that the post receptor defect is localized proximal to the cfos promoter itself. Abundances of the transcription factors Elk-1 and SRF being major players in coupling of MAPKs to cfos promoter activation were not altered. However, basal and inducible phosphorylation of Elk-1 was impaired. In addition, basal and stimulated transcriptional activity mediated by Elk-1 was almost abolished in patient cells. Therefore these results identify a post receptor defect in cFos induction, which appears to be related to a functional alteration of Elk-1. A possible relation of this signal transduction defect to the specific premature aging syndrome remains to be elucidated.

Adult↗
PubMed1984

The Wiedemann-Rautenstrauch or neonatal progeroid syndrome. Neuropathological study of a case.

Neuropathological data from the autopsy of a 5 1/2 year-old female patient with the Wiedemann-Rautenstrauch or neonatal progeroid syndrome are reported. Extensive demyelination is found in the central nervous system with occasionally a tigroid pattern and with large amounts of neutral fats and intermediate debris of myelin breakdown in macrophages. These lesions are characteristic of pure sudanophilic leucodystrophy. Features differentiating the findings from those in Pelizaeus-Merzbacher disease and in other disorders associated with sudanophilic leucodystrophy with various special characteristics are presented and discussed.

Brain↗
PubMed1985

[Ocular findings in Barsy syndrome].

Report on a male newborn with progeroid aspect, cutis laxa, intrauterine growth retardation, bilateral dislocation of the hip, generalized anomalies of ossification, peripheral corneal opacification comparable to corneal senile arcus, a diffuse, very discrete clouding of the stroma and an anterior polar cataract OD. Diagnosis and differential diagnosis of other progeroid and cutis laxa syndromes are discussed on the basis of the corresponding ocular findings.

Corneal Opacity↗
PubMed1979

Primary defect of insulin receptors in skin fibroblasts cultured from an infant with leprechaunism and insulin resistance.

Insulin binding to insulin receptors, on skin fibroblasts established in culture from an infant with insulin resistance and clinical features of leprechaunism was markedly decreased in comparison with cultures from an age-matched control. By contrast, the binding of epidermal growth factor, a polypeptide growth factor chemically unrelated to insulin, to patient's and control fibroblasts was indistinguishable. The selective defect in insulin binding to patient's fibroblasts was reflected in an impaired ability of insulin to stimulate 2-deoxyglucose uptake. These results most likely indicate a primary genetic defect of insulin receptors.

Biological Transport↗