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Review
. 2019 Feb 27;11(3):504.
doi: 10.3390/nu11030504.

Cytoplasmic and Mitochondrial NADPH-Coupled Redox Systems in the Regulation of Aging

Patrick C Bradshaw  1
Affiliations
Review

Cytoplasmic and Mitochondrial NADPH-Coupled Redox Systems in the Regulation of Aging

Patrick C Bradshaw. Nutrients. .

Abstract

The reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) protects against redox stress by providing reducing equivalents to antioxidants such as glutathione and thioredoxin. NADPH levels decline with aging in several tissues, but whether this is a major driving force for the aging process has not been well established. Global or neural overexpression of several cytoplasmic enzymes that synthesize NADPH have been shown to extend lifespan in model organisms such as Drosophila suggesting a positive relationship between cytoplasmic NADPH levels and longevity. Mitochondrial NADPH plays an important role in the protection against redox stress and cell death and mitochondrial NADPH-utilizing thioredoxin reductase 2 levels correlate with species longevity in cells from rodents and primates. Mitochondrial NADPH shuttles allow for some NADPH flux between the cytoplasm and mitochondria. Since a decline of nicotinamide adenine dinucleotide (NAD⁺) is linked with aging and because NADP⁺ is exclusively synthesized from NAD⁺ by cytoplasmic and mitochondrial NAD⁺ kinases, a decline in the cytoplasmic or mitochondrial NADPH pool may also contribute to the aging process. Therefore pro-longevity therapies should aim to maintain the levels of both NAD⁺ and NADPH in aging tissues.

Keywords: C. elegans; Drosophila; NADP; NADPH; aging; glutathione; lifespan; longevity; mitochondrial; nicotinamide adenine dinucleotide phosphate; redox; thioredoxin.

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Conflict of interest statement

The author declares no conflict of interest. The funders had no role in the writing of the manuscript or in the decision to publish.

Figures

Figure 1
Figure 1
Cytoplasmic and mitochondrial reduced nicotinamide adenine dinucleotide phosphate (NADPH)-linked redox systems. NADK: nicotinamide adenine dinucleotide (NAD+) kinase; ETC: electron transport chain; GSR: glutathione reductase; GSH: reduced glutathione; GSSG: oxidized glutathione disulfide; GPX: glutathione peroxidase; TXN: thioredoxin; TXNRD: thioredoxin reductase; PRDX: peroxiredoxin; H2O2: hydrogen peroxide; O2−: superoxide; G6PD: glucose-6-phosphate dehydrogenase; 6PGD: 6-phosphogluconate dehydrogenase; IDH: isocitrate dehydrogenase; ME: malic enzyme ALDH: aldehyde dehydrogenase; MTHFD: methylenetetrahydrofolate dehydrogenase; NNT: nicotinamide nucleotide transhydrogenase.
See this image and copyright information in PMC

References

    1. Aw T.Y. Postnatal Changes in Pyridine Nucleotides in Rat Hepatocytes: Composition and O2 Dependence. Pediatr. Res. 1991;30:112–117. doi: 10.1203/00006450-199107000-00022. - DOI - PubMed
    1. Ghosh D., Levault K.R., Brewer G.J. Relative importance of redox buffers GSH and NAD(P)H in age-related neurodegeneration and Alzheimer disease-like mouse neurons. Aging Cell. 2014;13:631–640. doi: 10.1111/acel.12216. - DOI - PMC - PubMed
    1. Zhu X.H., Lu M., Lee B.Y., Ugurbil K., Chen W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc. Natl. Acad. Sci. USA. 2015;112:2876–2881. doi: 10.1073/pnas.1417921112. - DOI - PMC - PubMed
    1. Lenaz G., D’Aurelio M., Merlo Pich M., Genova M.L., Ventura B., Bovina C., Formiggini G., Parenti Castelli G. Mitochondrial bioenergetics in aging. Biochim. Biophys. Acta. 2000;1459:397–404. doi: 10.1016/S0005-2728(00)00177-8. - DOI - PubMed
    1. Baciou L., Masoud R., Souabni H., Serfaty X., Karimi G., Bizouarn T., Houee Levin C. Phagocyte NADPH oxidase, oxidative stress and lipids: Anti- or pro ageing? Mech. Ageing Dev. 2018;172:30–34. doi: 10.1016/j.mad.2017.11.001. - DOI - PubMed

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