ascorbic-acid and Aging--Premature

Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many phenotypic features of WS. Importantly, mutant Wrn(Deltahel/Deltahel) mice show abnormal increases in visceral fat deposition and fasting blood triglyceride levels followed by insulin resistance and high blood glucose levels. These mice also exhibit increased heart and liver tissue reactive oxygen species concomitantly with oxidative DNA damage, indicating a pro-oxidant status. We treated mice with either ascorbate or catechin hydrate for 9 months. Vitamin C supplementation reduced oxidative stress in liver and heart tissues and reversed hypertriglyceridemia, hyperglycemia, and insulin resistance and reduced fat weight in mutant Wrn(Deltahel/Deltahel) mice. Although the free scavenger catechin hydrate also reduced oxidative DNA damage in heart and liver tissues, it did not reverse any of the metabolic phenotype aspects in treated mutant mice. Finally, vitamin C and catechin hydrate did not affect the metabolic status of wild-type mice. These results indicate that vitamin C supplementation could be beneficial for WS patients.

Topics: Aging, Premature; Animals; Ascorbic Acid; Catechin; DNA Damage; DNA Helicases; Free Radical Scavengers; Humans; Hyperglycemia; Hypertriglyceridemia; Insulin Resistance; Mice; Mutation; Oxidative Stress; Reactive Oxygen Species; RecQ Helicases; Werner Syndrome; Werner Syndrome Helicase

Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.

Topics: Aging; Aging, Premature; Ascorbic Acid; Cell Line; Cell Proliferation; Cellular Senescence; Humans; Mesenchymal Stem Cells; Models, Biological; Progeria; Quercetin; Werner Syndrome

The mitochondrial succinate dehydrogenase (SDH) is an iron-sulfur flavoenzyme linking the Krebs cycle and the mitochondrial respiratory chain. Mutations in the human SDHB, SDHC and SDHD genes are responsible for the development of paraganglioma and pheochromocytoma, tumors of the head and neck or the adrenal medulla, respectively. In recent years, SDH has become recognized as a source of reactive oxygen species, which may contribute to tumorigenesis. We have developed a Caenorhabditis elegans model to investigate the molecular and catalytic effects of mutations in the sdhb-1 gene, which encodes the SDH iron-sulfur subunit. We created mutations in Pro211; this residue is located near the site of ubiquinone reduction and is conserved in human SDHB (Pro197), where it is associated with tumorigenesis. Mutant phenotypes ranged from relatively benign to lethal and were characterized by hypersensitivity to oxidative stress, a shortened life span, impaired respiration and overproduction of superoxide. Our data suggest that the SDH ubiquinone-binding site can become a source of superoxide and that the pathological consequences of SDH mutations can be mitigated with antioxidants, such as ascorbate and N-acetyl-l-cysteine. Our work leads to a better understanding of the relationship between genotype and phenotype in respiratory chain mutations and of the mechanisms of aging and tumorigenesis.

Topics: Acetylcysteine; Aging, Premature; Amino Acid Sequence; Animals; Animals, Genetically Modified; Antioxidants; Ascorbic Acid; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Respiration; DNA Mutational Analysis; Herbicides; Humans; Life Expectancy; Models, Molecular; Molecular Sequence Data; Mutation; Oxidative Stress; Paraquat; Phenotype; Protein Conformation; Protein Subunits; Reactive Oxygen Species; Sequence Alignment; Succinate Dehydrogenase; Superoxides

Topics: Aged; Aged, 80 and over; Aging, Premature; Ascorbic Acid; Depression; Depressive Disorder; Procaine; Substance-Related Disorders; Vitamin B Complex