Baricitinib, a JAK-STAT Inhibitor, Reduces the Cellular Toxicity of the Farnesyltransferase Inhibitor Lonafarnib in Progeria Cells.

Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare multisystem premature aging disorder that leads to early death (mean age of 14.7 years) due to myocardial infarction or stroke. Most cases have a de novo point mutation at position G608G within exon 11 of the LMNA gene. This mutation leads to the production of a permanently farnesylated truncated prelamin A protein called "progerin" that is toxic to the cells. Recently, farnesyltransferase inhibitor (FTI) lonafarnib has been approved by the FDA for the treatment of patients with HGPS. While lonafarnib treatment irrefutably ameliorates HGPS disease, it is however not a cure. FTI has been shown to cause several cellular side effects, including genomic instability as well as binucleated and donut-shaped nuclei. We report that, in addition to these cellular stresses, FTI caused an increased frequency of cytosolic DNA fragment formation. These extranuclear DNA fragments colocalized with cGAs and activated the cGAS-STING-STAT1 signaling axis, upregulating the expression of proinflammatory cytokines in FTI-treated human HGPS fibroblasts. Treatment with lonafarnib and baricitinib, a JAK-STAT inhibitor, not only prevented the activation of the cGAS STING-STAT1 pathway, but also improved the overall HGPS cellular homeostasis. These ameliorations included progerin levels, nuclear shape, proteostasis, cellular ATP, proliferation, and the reduction of cellular inflammation and senescence. Thus, we suggest that combining lonafarnib with baricitinib might provide an opportunity to reduce FTI cellular toxicity and ameliorate HGPS symptoms further than lonafarnib alone.

Redox imbalance in a model of rat mimicking Hutchinson-Gilford progeria syndrome.

Although several etiological factors contribute to the complexity of the aging process, the ultimate component of macromolecular damage and consequent cell death involves the altered redox balance inclined towards increased ROS production and/or decreased antioxidant protection. Given that, the chronic dihydrotachysterol (DHT) intoxication in rats induce Hutchinson Gilford progeria like syndrome, the present study provides the evidence for altered redox balance as evidenced by alteration in parameters of oxidative stress in blood plasma and erythrocytes including MDA, GSH, FRAP AOPP PMRS, AGEs, AChE and osmotic fragility which substantiate the suitability of the model for aging studies.

Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 4. Age-related eye disease. SkQ1 returns vision to blind animals.

Mitochondria-targeted cationic plastoquinone derivative SkQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) has been investigated as a potential tool for treating a number of ROS-related ocular diseases. In OXYS rats suffering from a ROS-induced progeria, very small amounts of SkQ1 (50 nmol/kg per day) added to food were found to prevent development of age-induced cataract and retinopathies of the eye, lipid peroxidation and protein carbonylation in skeletal muscles, as well as a decrease in bone mineralization. Instillation of drops of 250 nM SkQ1 reversed cataract and retinopathies in 3-12-month-old (but not in 24-month-old) OXYS rats. In rabbits, experimental uveitis and glaucoma were induced by immunization with arrestin and injections of hydroxypropyl methyl cellulose to the eye anterior sector, respectively. Uveitis was found to be prevented or reversed by instillation of 250 nM SkQ1 drops (four drops per day). Development of glaucoma was retarded by drops of 5 microM SkQ1 (one drop daily). SkQ1 was tested in veterinarian practice. A totally of 271 animals (dogs, cats, and horses) suffering from retinopathies, uveitis, conjunctivitis, and cornea diseases were treated with drops of 250 nM SkQ1. In 242 cases, positive therapeutic effect was obvious. Among animals suffering from retinopathies, 89 were blind. In 67 cases, vision returned after SkQ1 treatment. In ex vivo studies of cultivated posterior retina sector, it was found that 20 nM SkQ1 strongly decreased macrophagal transformation of the retinal pigmented epithelial cells, an effect which might explain some of the above SkQ1 activities. It is concluded that low concentrations of SkQ1 are promising in treating retinopathies, cataract, uveitis, glaucoma, and some other ocular diseases.

Effect of Tokaj wine in combination with water and 10% alcohol solution on long-life and development of alcohol progeria in Wistar SPF rats.

Whole-life consumption of the pure Tokaj wine (The Furmint variety) with documented antioxidative activity significantly elongated (p<0.05) the life of laboratory animals in comparison to the control group consuming water and in comparison to group consuming ethanol (10%). Whole-life intake of ethanol (10%) diluted with water neither shortened nor elongated life of laboratory animals in comparison to control group consuming water. An increased dosing of the Tokaj wine combined with water shortened life expectation (p<0.001). Obviously mixing of wine and water increases the absorption of toxic elements influenced by an acid medium through the change of anions to cations, but also increased appetite resulting into obesity on the basis of hyperphagia.

Premature aging in female alcoholics. A neuropsychological study.

The hypothesis of premature aging in middle-aged female alcoholics was tested by comparing their level pattern of neuropsychological test performance with age-equated nonalcoholic females and elderly nonalcoholic women. Alcoholics had significantly poorer performance on the tests than nonalcoholic peers but performed significantly better than the elderly. A subsample of more severe alcoholics was not significantly different from the elderly in level of performance although they were approximately 20 years younger. However, there were no differences among the groups in pattern of test performance. The data on level of performance partially support the hypothesis of premature aging in alcoholics. Stronger support would be attained if it were demonstrated that the alcoholics and elderly have a similar impairment in the neuropsychological processes eventuating in lowered performance.

Examination of dihydrotachysterol-induced progeria as a model for aging changes in carbohydrate metabolism.

Interest in the pharmacological effects of drugs in the elderly has created a need for a laboratory model in which responses of aged animals to drugs can be studied. Dihydrotachysterol (DHT)-induced progeria, a syndrome with symptoms similar to those seen in normal aging, was evaluated as an old age model. DHT-treatment was shown to produce a decreased carbohydrate tolerance that was due to an impaired release of insulin from pancreatic islets and not due to a decreased sensitivity to insulin. These changes were unlike those observed with aging. Thus, DHT-induced progeria would not appear to be a good model for aging for the investigation of carbohydrate metabolism. Evidence is presented which indicates that glucose and tolbutamide act via different mechanism to stimulate insulin release.

Experimental pathology of aging.

We have been concerned in the first section of this review with those diseases that are aging processes, or appear to be so. Some of these (e.g., cardiovascular, pulmonary, neoplasia) cause the death of a large proportion of animals, while others (e.g., osteoporosis, amyloidosis), though clearly progressive with age, are nonfatal. Many diverse factors influence the normal process of aging. Restriction of dietary caloric intake prolongs lifespan and decreases the incidence and severity of diseases associated with aging, probably by depressing anterior pituitary gland function...