Data from our laboratory and others, have demonstrated that the plasma membrane redox system is, at least in part, responsible of the maintenance of the antioxidant capacity during oxidative stress challenges induced by the diet and aging. The upregulation of the plasma membrane redox system that occurs during CR decreases the levels of oxidative stress in aged membranes. CR extends life span of yeasts by decreasing NADH levels, which would connect this intervention to plasma membrane NADH-dependent dehydrogenases. CR modifies composition of fatty acid in the plasma membrane, resulting in decreased oxidative damage including lipid peroxidation. More importantly, plasma membrane redox activities and also the content of CoQ, which decline with age, are enhanced by CR providing protection to phospholipids and preventing the lipid peroxidation reaction progression. We are focusing our efforts on the generation of transgenic and knock out animals of the different dehydrogenases involved in this antioxidant system. We have successfully created NQO1 and Cyt-b5-reductase overexpressors and obtained NQO1 and NRF2 KO animals. We are setting longevity studies as well as short term interventions to fully characterize these new mouse lines. In collaboration with the laboratory of Dr. Placido Navas we have shown that the Saccharomyces cerevisiae homolog of Cyt-b5-reductase, NQR1, resides at the plasma membrane and when overexpressed extends both replicative and chronological lifespan. We demonstrated that NQR1 extends replicative lifespan in a SIR2-dependent manner by shifting cells towards respiratory metabolism and decreasing the pyridine nucleotide pool without altering the NAD+/NADH ratio. Chronological lifespan extension, in contrast, occurs via a SIR2-independent decrease in ethanol production. We conclude that NQR1 is a key mediator of lifespan extension by CR through its effects on yeast metabolism and discuss how these findings could suggest a function for this protein in lifespan extension in mammals. We now have extended our previous observations on NQO1 and we are now demonstrating an important novel physiological role for NQO1. We have determined that NQO1 is a target if the insulin receptor which shifts its cellular localization by phosphorylation. NQO1 overexpression shifted the physiology of mice on a high fat diet towards that of mice on a standard diet. These phenomena occur through the NQO1-mediated reduction in oxidative stress damage and prevention of the activation of the proinflammatory NFκβpathway.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000362-05
Application #
8552382
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$389,240
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Ingram, Donald K; de Cabo, Rafael (2017) Calorie restriction in rodents: Caveats to consider. Ageing Res Rev 39:15-28
Ariza, Julia; González-Reyes, José A; Jódar, Laura et al. (2016) Mitochondrial permeabilization without caspase activation mediates the increase of basal apoptosis in cells lacking Nrf2. Free Radic Biol Med 95:82-95
Di Biase, Stefano; Lee, Changhan; Brandhorst, Sebastian et al. (2016) Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity. Cancer Cell 30:136-146
Allard, Joanne S; Perez, Evelyn J; Fukui, Koji et al. (2016) Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice. Behav Brain Res 301:1-9
Martin-Montalvo, Alejandro; Sun, Yaning; Diaz-Ruiz, Alberto et al. (2016) Cytochrome b5 reductase and the control of lipid metabolism and healthspan. NPJ Aging Mech Dis 2:16006
Di Francesco, Andrea; Di Germanio, Clara; Panda, Amaresh C et al. (2016) Novel RNA-binding activity of NQO1 promotes SERPINA1 mRNA translation. Free Radic Biol Med 99:225-233
Villalba, José Manuel; López-Domínguez, José Alberto; Chen, Yana et al. (2015) The influence of dietary fat source on liver and skeletal muscle mitochondrial modifications and lifespan changes in calorie-restricted mice. Biogerontology 16:655-70
Gonzalez-Freire, Marta; de Cabo, Rafael; Bernier, Michel et al. (2015) Reconsidering the Role of Mitochondria in Aging. J Gerontol A Biol Sci Med Sci 70:1334-42
Siendones, Emilio; SantaCruz-Calvo, Sara; Martín-Montalvo, Alejandro et al. (2014) Membrane-bound CYB5R3 is a common effector of nutritional and oxidative stress response through FOXO3a and Nrf2. Antioxid Redox Signal 21:1708-25
Fernández-Ayala, Daniel J M; Guerra, Ignacio; Jiménez-Gancedo, Sandra et al. (2013) Survival transcriptome in the coenzyme Q10 deficiency syndrome is acquired by epigenetic modifications: a modelling study for human coenzyme Q10 deficiencies. BMJ Open 3:

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