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Age- and AD-related redox state of NADH in subcellular compartments by fluorescence lifetime imaging microscopy

  • Yue Dong
  • Michelle A. Digman
  • Gregory J. BrewerEmail author
Original Article
  • 14 Downloads

Abstract

Nicotinamide adenine dinucleotide (reduced form: NADH) serves as a vital redox-energy currency for reduction-oxidation homeostasis and fulfilling energetic demands. While NADH exists as free and bound forms, only free NADH is utilized for complex I to power oxidative phosphorylation, especially important in neurons. Here, we studied how much free NADH remains available for energy production in mitochondria of old living neurons. We hypothesize that free NADH in neurons from old mice is lower than the levels in young mice and even lower in neurons from the 3xTg-AD Alzheimer’s disease (AD) mouse model. To assess free NADH, we used lifetime imaging of NADH autofluorescence with 2-photon excitation to be able to resolve the pool of NADH in mitochondria, cytoplasm, and nuclei. Primary neurons from old mice were characterized by a lower free/bound NADH ratio than young neurons from both non-transgenic (NTg) and more so in 3xTg-AD mice. Mitochondrial compartments maintained 26 to 41% more reducing NADH redox state than cytoplasm for each age, genotype, and sex. Aging diminished the mitochondrial free NADH concentration in NTg neurons by 43% and in 3xTg-AD by 50%. The lower free NADH with age suggests a decline in capacity to regenerate free NADH for energetic supply to power oxidative phosphorylation which further worsens in AD. Applying this non-invasive approach, we showed the most explicit measures yet of bioenergetic deficits in free NADH with aging at the subcellular level in live neurons from in-bred mice and an AD model.

Keywords

NADH Aging brain Alzheimer’s disease FLIM Mitochondria Redox states 

Notes

Acknowledgements

We appreciate Prof. Enrico Gratton for inspirational discussions and the help of Rachel Cinco-Hedde, Ning Ma, and Sara Sameni at Laboratory for Fluorescence Dynamics, UC Irvine.

Funding information

This work was supported by the UC Irvine Foundation, NIH P41-GM103540 and a grant from the NIH RF1 AG058218.

References

  1. Alzheimer’s A (2016) 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 12:459–509Google Scholar
  2. Aon MA, Cortassa S, O’Rourke B (2010) Redox-optimized ROS balance: a unifying hypothesis. Biochim Biophys Acta 1797:865–877.  https://doi.org/10.1016/j.bbabio.2010.02.016 Google Scholar
  3. Attwell D, Laughlin SB (2001) An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 21:1133–1145.  https://doi.org/10.1097/00004647-200110000-00001 Google Scholar
  4. Bai P, Canto C (2012) The role of PARP-1 and PARP-2 enzymes in metabolic regulation and disease. Cell Metab 16:290–295.  https://doi.org/10.1016/j.cmet.2012.06.016 Google Scholar
  5. Barnett A, Brewer GJ (2011) Autophagy in aging and Alzheimer’s disease: pathologic or protective? J Alzheimers Dis 25:385–394.  https://doi.org/10.3233/JAD-2011-101989 Google Scholar
  6. Berger F, Lau C, Dahlmann M, Ziegler M (2005) Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J Biol Chem 280:36334–36341.  https://doi.org/10.1074/jbc.M508660200 Google Scholar
  7. Bird DK, Yan L, Vrotsos KM, Eliceiri KW, Vaughan EM, Keely PJ, White JG, Ramanujam N (2005) Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme. NADH. Cancer Res 65:8766–8773.  https://doi.org/10.1158/0008-5472.CAN-04-3922 Google Scholar
  8. Borras C, Sastre J, Garcia-Sala D, Lloret A, Pallardo FV, Vina J (2003) Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radic Biol Med 34:546–552Google Scholar
  9. Brewer GJ (1997) Isolation and culture of adult rat hippocampal neurons. J Neurosci Methods 71:143–155Google Scholar
  10. Brewer GJ (1998) Age-related toxicity to lactate, glutamate, and beta-amyloid in cultured adult neurons. Neurobiol Aging 19:561–568Google Scholar
  11. Brewer GJ (2010) Epigenetic oxidative redox shift (EORS) theory of aging unifies the free radical and insulin signaling theories. Exp Gerontol 45:173–179.  https://doi.org/10.1016/j.exger.2009.11.007 Google Scholar
  12. Brewer GJ, Torricelli JR (2007) Isolation and culture of adult neurons and neurospheres. Nat Protoc 2:1490–1498.  https://doi.org/10.1038/nprot.2007.207 Google Scholar
  13. Brewer GJ, Reichensperger JD, Brinton RD (2006) Prevention of age-related dysregulation of calcium dynamics by estrogen in neurons. Neurobiol Aging 27:306–317.  https://doi.org/10.1016/j.neurobiolaging.2005.01.019 Google Scholar
  14. Brewer GJ, Boehler MD, Pearson RA, DeMaris AA, Ide AN, Wheeler BC (2009) Neuron network activity scales exponentially with synapse density. J Neural Eng 6:014001.  https://doi.org/10.1088/1741-2560/6/1/014001 Google Scholar
  15. Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE (2005) Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol 57:695–703.  https://doi.org/10.1002/ana.20474 Google Scholar
  16. Cady C, Evans MS, Brewer GJ (2001) Age-related differences in NMDA responses in cultured rat hippocampal neurons. Brain Res 921:1–11Google Scholar
  17. Calkins MJ, Manczak M, Mao P, Shirendeb U, Reddy PH (2011) Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. Hum Mol Genet 20:4515–4529.  https://doi.org/10.1093/hmg/ddr381 Google Scholar
  18. Camacho-Pereira J, Tarragó MG, Chini CCS, Nin V, Escande C, Warner GM, Puranik AS, Schoon RA, Reid JM, Galina A, Chini EN (2016) CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab 23:1127–1139.  https://doi.org/10.1016/j.cmet.2016.05.006 Google Scholar
  19. Canto C et al (2010) Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 11:213–219.  https://doi.org/10.1016/j.cmet.2010.02.006 Google Scholar
  20. Caro P et al. (2009) Effect of 40% restriction of dietary amino acids (except methionine) on mitochondrial oxidative stress and biogenesis, AIF and SIRT1 in rat liver Biogerontology 10:579–592.  https://doi.org/10.1007/s10522-008-9200-4
  21. Chance B, Thorell B (1959) Localization and kinetics of reduced pyridine nucleotide in living cells by microfluorometry. J Biol Chem 234:3044–3050Google Scholar
  22. Christensen CE, Karlsson M, Winther JR, Jensen PR, Lerche MH (2014) Non-invasive in-cell determination of free cytosolic [NAD+]/[NADH] ratios using hyperpolarized glucose show large variations in metabolic phenotypes. J Biol Chem 289:2344–2352.  https://doi.org/10.1074/jbc.M113.498626 Google Scholar
  23. Coremans JM, Ince C, Bruining HA, Puppels GJ (1997) (Semi-)quantitative analysis of reduced nicotinamide adenine dinucleotide fluorescence images of blood-perfused rat heart. Biophys J 72:1849–1860.  https://doi.org/10.1016/S0006-3495(97)78831-3 Google Scholar
  24. Datta R, Alfonso-Garcia A, Cinco R, Gratton E (2015) Fluorescence lifetime imaging of endogenous biomarker of oxidative stress. Sci Rep 5:9848.  https://doi.org/10.1038/srep09848 Google Scholar
  25. David DC, Hauptmann S, Scherping I, Schuessel K, Keil U, Rizzu P, Ravid R, Dröse S, Brandt U, Müller WE, Eckert A, Götz J (2005) Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem 280:23802–23814.  https://doi.org/10.1074/jbc.M500356200 Google Scholar
  26. Easlon E, Tsang F, Skinner C, Wang C, Lin SJ (2008) The malate-aspartate NADH shuttle components are novel metabolic longevity regulators required for calorie restriction-mediated life span extension in yeast. Genes Dev 22:931–944.  https://doi.org/10.1101/gad.1648308 Google Scholar
  27. Eng J, Lynch RM, Balaban RS (1989) Nicotinamide adenine dinucleotide fluorescence spectroscopy and imaging of isolated cardiac myocytes. Biophys J 55:621–630.  https://doi.org/10.1016/S0006-3495(89)82859-0 Google Scholar
  28. Evans MS, Collings MA, Brewer GJ (1998) Electrophysiology of embryonic, adult and aged rat hippocampal neurons in serum-free culture J Neurosci Meth 79:37–46Google Scholar
  29. Fattoretti P, Balietti M, Casoli T, Giorgetti B, di Stefano G, Bertoni-Freddari C, Lattanzio F, Sensi SL (2010) Decreased numeric density of succinic dehydrogenase-positive mitochondria in CA1 pyramidal neurons of 3xTg-AD mice. Rejuvenation Res 13:144–147.  https://doi.org/10.1089/rej.2009.0937 Google Scholar
  30. Figueiredo PA, Powers SK, Ferreira RM, Amado F, Appell HJ, Duarte JA (2009) Impact of lifelong sedentary behavior on mitochondrial function of mice skeletal muscle. J Gerontol A Biol Sci Med Sci 64:927–939.  https://doi.org/10.1093/gerona/glp066 Google Scholar
  31. Ghosh D, LeVault KR, Barnett AJ, Brewer GJ (2012) A reversible early oxidized redox state that precedes macromolecular ROS damage in aging nontransgenic and 3xTg-AD mouse neurons. J Neurosci 32:5821–5832.  https://doi.org/10.1523/JNEUROSCI.6192-11.2012 Google Scholar
  32. Ghosh D, Levault KR, Brewer GJ (2014) Relative importance of redox buffers GSH and NAD(P) H in age-related neurodegeneration and Alzheimer disease-like mouse neurons. Aging Cell 13:631–640.  https://doi.org/10.1111/acel.12216 Google Scholar
  33. Gibson GE, Blass JP (1976) Impaired synthesis of acetylcholine in brain accompanying mild hypoxia and hypoglycemia. J Neurochem 27:37–42Google Scholar
  34. Gomes AP, Price NL, Ling AJY, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA (2013) Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155:1624–1638.  https://doi.org/10.1016/j.cell.2013.11.037 Google Scholar
  35. Green KN, LaFerla FM (2008) Linking calcium to Abeta and Alzheimer’s disease. Neuron 59:190–194.  https://doi.org/10.1016/j.neuron.2008.07.013 Google Scholar
  36. Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM (2008) Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci 28:11500–11510.  https://doi.org/10.1523/JNEUROSCI.3203-08.2008 Google Scholar
  37. Grimm A, Eckert A (2017) Brain aging and neurodegeneration: from a mitochondrial point of view. J Neurochem 143:418–431.  https://doi.org/10.1111/jnc.14037 Google Scholar
  38. Guebel DV, Torres NV (2016) Sexual dimorphism and aging in the human hyppocampus: identification, validation, and impact of differentially expressed genes by factorial microarray and network analysis. Front Aging Neurosci 8:229.  https://doi.org/10.3389/fnagi.2016.00229 Google Scholar
  39. Guevara R, Santandreu FM, Valle A, Gianotti M, Oliver J, Roca P (2009) Sex-dependent differences in aged rat brain mitochondrial function and oxidative stress. Free Radic Biol Med 46:169–175.  https://doi.org/10.1016/j.freeradbiomed.2008.09.035 Google Scholar
  40. Hansen JM, Go YM, Jones DP (2006) Nuclear and mitochondrial compartmentation of oxidative stress and redox signaling. Annu Rev Pharmacol Toxicol 46:215–234.  https://doi.org/10.1146/annurev.pharmtox.46.120604.141122 Google Scholar
  41. Hayashida S, Arimoto A, Kuramoto Y, Kozako T, Honda S, Shimeno H, Soeda S (2010) Fasting promotes the expression of SIRT1, an NAD+ -dependent protein deacetylase, via activation of PPARalpha in mice. Mol Cell Biochem 339:285–292.  https://doi.org/10.1007/s11010-010-0391-z Google Scholar
  42. Hou Y, Lautrup S, Cordonnier S, Wang Y, Croteau DL, Zavala E, Zhang Y, Moritoh K, O’Connell JF, Baptiste BA, Stevnsner TV, Mattson MP, Bohr VA (2018) NAD(+) supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A 115:E1876–E1885.  https://doi.org/10.1073/pnas.1718819115 Google Scholar
  43. Imam SZ, Karahalil B, Hogue BA, Souza-Pinto NC, Bohr VA (2006) Mitochondrial and nuclear DNA-repair capacity of various brain regions in mouse is altered in an age-dependent manner. Neurobiol Aging 27:1129–1136.  https://doi.org/10.1016/j.neurobiolaging.2005.06.002 Google Scholar
  44. Intlekofer KA, Berchtold NC, Malvaez M, Carlos AJ, McQuown SC, Cunningham MJ, Wood MA, Cotman CW (2013) Exercise and sodium butyrate transform a subthreshold learning event into long-term memory via a brain-derived neurotrophic factor-dependent mechanism. Neuropsychopharmacology 38:2027–2034.  https://doi.org/10.1038/npp.2013.104 Google Scholar
  45. Jones TT, Brewer GJ (2010) Age-related deficiencies in complex I endogenous substrate availability and reserve capacity of complex IV in cortical neuron electron transport. Biochim Biophys Acta 1797:167–176.  https://doi.org/10.1016/j.bbabio.2009.09.009 Google Scholar
  46. Klaidman LK, Leung AC, Adams JD Jr (1995) High-performance liquid chromatography analysis of oxidized and reduced pyridine dinucleotides in specific brain regions. Anal Biochem 228:312–317.  https://doi.org/10.1006/abio.1995.1356 Google Scholar
  47. Koch-Nolte F, Fischer S, Haag F, Ziegler M (2011) Compartmentation of NAD+-dependent signalling. FEBS Lett 585:1651–1656.  https://doi.org/10.1016/j.febslet.2011.03.045 Google Scholar
  48. Lakowicz JR, Szmacinski H, Nowaczyk K, Johnson ML (1992) Fluorescence lifetime imaging of free and protein-bound. NADH Proc Natl Acad Sci U S A 89:1271–1275Google Scholar
  49. Lavrovsky Y, Chatterjee B, Clark RA, Roy AK (2000) Role of redox-regulated transcription factors in inflammation, aging and age-related diseases. Exp Gerontol 35:521–532Google Scholar
  50. Lee Y, Kim J, Han ES, Chae S, Ryu M, Ahn KH, Park EJ (2015) Changes in physical activity and cognitive decline in older adults living in the community. Age (Dordr) 37:20.  https://doi.org/10.1007/s11357-015-9759-z Google Scholar
  51. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795.  https://doi.org/10.1038/nature05292 Google Scholar
  52. Liu D, Pitta M, Jiang H, Lee JH, Zhang G, Chen X, Kawamoto EM, Mattson MP (2013) Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: evidence for improved neuronal bioenergetics and autophagy procession. Neurobiol Aging 34:1564–1580.  https://doi.org/10.1016/j.neurobiolaging.2012.11.020 Google Scholar
  53. Lopez-Torres M, Barja G (2008) Lowered methionine ingestion as responsible for the decrease in rodent mitochondrial oxidative stress in protein and dietary restriction possible implications for humans. Biochim Biophys Acta 1780:1337–1347.  https://doi.org/10.1016/j.bbagen.2008.01.007 Google Scholar
  54. Ma N, Digman MA, Malacrida L, Gratton E (2016) Measurements of absolute concentrations of NADH in cells using the phasor. FLIM method. Biomed Opt Express 7:2441–2452.  https://doi.org/10.1364/BOE.7.002441 Google Scholar
  55. Manczak M, Reddy PH (2012) Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer’s disease neurons: implications for mitochondrial dysfunction and neuronal damage. Hum Mol Genet 21:2538–2547.  https://doi.org/10.1093/hmg/dds072 Google Scholar
  56. Martin SA et al (2016) Regional metabolic heterogeneity of the hippocampus is nonuniformly impacted by age and caloric restriction. Aging Cell 15:100–110.  https://doi.org/10.1111/acel.12418 Google Scholar
  57. Martins IV, Rivers-Auty J, Allan SM, Lawrence CB (2017) Mitochondrial abnormalities and synaptic loss underlie memory deficits seen in mouse models of obesity and Alzheimer’s disease. J Alzheimers Dis 55:915–932.  https://doi.org/10.3233/JAD-160640 Google Scholar
  58. Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Cantó C, Mottis A, Jo YS, Viswanathan M, Schoonjans K, Guarente L, Auwerx J (2013) The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO. Signal Cell 154:430–441.  https://doi.org/10.1016/j.cell.2013.06.016 Google Scholar
  59. Nakagawa T, Lomb DJ, Haigis MC, Guarente L (2009) SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 137:560–570.  https://doi.org/10.1016/j.cell.2009.02.026 Google Scholar
  60. Naudi A et al (2007) Methionine restriction decreases endogenous oxidative molecular damage and increases mitochondrial biogenesis and uncoupling protein 4 in rat brain. Rejuvenation Res 10:473–484.  https://doi.org/10.1089/rej.2007.0538 Google Scholar
  61. Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nat Med 19:983–997.  https://doi.org/10.1038/nm.3232 Google Scholar
  62. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421Google Scholar
  63. Parihar MS, Kunz EA, Brewer GJ (2008) Age-related decreases in NAD(P) H and glutathione cause redox declines before ATP loss during glutamate treatment of hippocampal neurons. J Neurosci Res 86:2339–2352.  https://doi.org/10.1002/jnr.21679 Google Scholar
  64. Patel JR, Brewer GJ (2003) Age-related changes in neuronal glucose uptake in response to glutamate and beta-amyloid. J Neurosci Res 72:527–536.  https://doi.org/10.1002/jnr.10602 Google Scholar
  65. Pittelli M, Felici R, Pitozzi V, Giovannelli L, Bigagli E, Cialdai F, Romano G, Moroni F, Chiarugi A (2011) Pharmacological effects of exogenous NAD on mitochondrial bioenergetics, DNA repair, and apoptosis. Mol Pharmacol 80:1136–1146.  https://doi.org/10.1124/mol.111.073916 Google Scholar
  66. Prolla TA, Denu JM (2014) NAD+ deficiency in age-related mitochondrial dysfunction. Cell Metab 19:178–180.  https://doi.org/10.1016/j.cmet.2014.01.005 Google Scholar
  67. Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM (2006) Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem 281:21745–21754.  https://doi.org/10.1074/jbc.M602909200 Google Scholar
  68. Revollo JR, Grimm AA, Imai S (2004) The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem 279:50754–50763.  https://doi.org/10.1074/jbc.M408388200 Google Scholar
  69. Rhein V, Eckert A (2007) Effects of Alzheimer’s amyloid-beta and tau protein on mitochondrial function -- role of glucose metabolism and insulin signalling. Arch Physiol Biochem 113:131–141.  https://doi.org/10.1080/13813450701572288 Google Scholar
  70. Ronchi JA, Francisco A, Passos LA, Figueira TR, Castilho RF (2016) The contribution of nicotinamide nucleotide transhydrogenase to peroxide detoxification is dependent on the respiratory state and counterbalanced by other sources of NADPH in liver mitochondria. J Biol Chem 291:20173–20187.  https://doi.org/10.1074/jbc.M116.730473 Google Scholar
  71. Sahar S, Nin V, Barbosa MT, Chini EN, Sassone-Corsi P (2011) Altered behavioral and metabolic circadian rhythms in mice with disrupted NAD+ oscillation. Aging (Albany NY) 3:794–802.  https://doi.org/10.18632/aging.100368 Google Scholar
  72. Schiff M, Benit P, Coulibaly A, Loublier S, El-Khoury R, Rustin P (2011) Mitochondrial response to controlled nutrition in health and disease. Nutr Rev 69:65–75.  https://doi.org/10.1111/j.1753-4887.2010.00363.x Google Scholar
  73. Shetty PK, Galeffi F, Turner DA (2014) Nicotinamide pre-treatment ameliorates NAD(H) hyperoxidation and improves neuronal function after severe hypoxia. Neurobiol Dis 62:469–478.  https://doi.org/10.1016/j.nbd.2013.10.025 Google Scholar
  74. Sporty JL, Kabir MM, Turteltaub KW, Ognibene T, Lin SJ, Bench G (2008) Single sample extraction protocol for the quantification of NAD and NADH redox states in Saccharomyces cerevisiae. J Sep Sci 31:3202–3211.  https://doi.org/10.1002/jssc.200800238 Google Scholar
  75. Squier TC (2001) Oxidative stress and protein aggregation during biological aging. Exp Gerontol 36:1539–1550Google Scholar
  76. Stolle S, Ciapaite J, Reijne AC, Talarovicova A, Wolters JC, Aguirre-Gamboa R, van der Vlies P, de Lange K, Neerincx PB, van der Vries G, Deelen P, Swertz MA, Li Y, Bischoff R, Permentier HP, Horvatovitch PL, Groen AK, van Dijk G, Reijngoud DJ, Bakker BM (2018) Running-wheel activity delays mitochondrial respiratory flux decline in aging mouse muscle via a post-transcriptional mechanism. Aging Cell 17.  https://doi.org/10.1111/acel.12700
  77. Stringari C, Nourse JL, Flanagan LA, Gratton E (2012) Phasor fluorescence lifetime microscopy of free and protein-bound NADH reveals neural stem cell differentiation potential. PLoS One 7:e48014.  https://doi.org/10.1371/journal.pone.0048014 Google Scholar
  78. Stringari C, Wang H, Geyfman M, Crosignani V, Kumar V, Takahashi JS, Andersen B, Gratton E (2015) In vivo single-cell detection of metabolic oscillations in stem cells. Cell Rep 10:1–7.  https://doi.org/10.1016/j.celrep.2014.12.007 Google Scholar
  79. Uppal A, Gupta PK (2003) Measurement of NADH concentration in normal and malignant human tissues from breast and oral cavity. Biotechnol Appl Biochem 37:45–50.  https://doi.org/10.1042/BA20020052 Google Scholar
  80. van Munster EB, Gadella TW (2005) Fluorescence lifetime imaging microscopy (FLIM). Adv Biochem Eng Biotechnol 95:143–175Google Scholar
  81. Verdin E (2015) NAD(+) in aging, metabolism, and neurodegeneration. Science 350:1208–1213.  https://doi.org/10.1126/science.aac4854 Google Scholar
  82. Walker MP, LaFerla FM, Oddo SS, Brewer GJ (2013) Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer’s disease. Age (Dordr) 35:519–531.  https://doi.org/10.1007/s11357-011-9375-5 Google Scholar
  83. Ward MW, Rego AC, Frenguelli BG, Nicholls DG (2000) Mitochondrial membrane potential and glutamate excitotoxicity in cultured cerebellar granule cells. J Neurosci 20:7208–7219Google Scholar
  84. Winkler U, Hirrlinger J (2015) Crosstalk of signaling and metabolism mediated by the NAD(+)/NADH redox state in brain cells. Neurochem Res 40:2394–2401.  https://doi.org/10.1007/s11064-015-1526-0 Google Scholar
  85. Xiao W, Wang RS, Handy DE, Loscalzo J (2018) NAD(H) and NADP(H) redox couples and cellular energy metabolism. Antioxid Redox Signal 28:251–272.  https://doi.org/10.1089/ars.2017.7216 Google Scholar
  86. Yang H, Yang T, Baur JA, Perez E, Matsui T, Carmona JJ, Lamming DW, Souza-Pinto NC, Bohr VA, Rosenzweig A, de Cabo R, Sauve AA, Sinclair DA (2007) Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130:1095–1107.  https://doi.org/10.1016/j.cell.2007.07.035 Google Scholar
  87. Yang L, Licastro D, Cava E, Veronese N, Spelta F, Rizza W, Bertozzi B, Villareal DT, Hotamisligil GS, Holloszy JO, Fontana L (2016) Long-term calorie restriction enhances cellular quality-control processes in human skeletal muscle. Cell Rep 14:422–428.  https://doi.org/10.1016/j.ce Google Scholar
  88. Yaniv Y, Juhaszova M, Sollott SJ (2013) Age-related changes of myocardial ATP supply and demand mechanisms. Trends Endocrinol Metab 24:495–505.  https://doi.org/10.1016/j.tem.2013.06.001 Google Scholar
  89. Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 106:14670–14675.  https://doi.org/10.1073/pnas.0903563106 Google Scholar
  90. Yao J, Irwin R, Chen S, Hamilton R, Cadenas E, Brinton RD (2012) Ovarian hormone loss induces bioenergetic deficits and mitochondrial beta-amyloid. Neurobiol Aging 33:1507–1521.  https://doi.org/10.1016/j.neurobiolaging.2011.03.001 Google Scholar
  91. Yu Q, Heikal AA (2009) Two-photon autofluorescence dynamics imaging reveals sensitivity of intracellular NADH concentration and conformation to cell physiology at the single-cell level. J Photochem Photobiol B 95:46–57.  https://doi.org/10.1016/j.jphotobiol.2008.12.010 Google Scholar
  92. Zhu XH, Lu M, Lee BY, Ugurbil K, Chen W (2015) In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc Natl Acad Sci U S A 112:2876–2881.  https://doi.org/10.1073/pnas.1417921112 Google Scholar

Copyright information

© American Aging Association 2019

Authors and Affiliations

  • Yue Dong
    • 1
  • Michelle A. Digman
    • 1
    • 2
  • Gregory J. Brewer
    • 1
    • 3
    Email author
  1. 1.Department of Biomedical EngineeringUniversity of California IrvineIrvineUSA
  2. 2.Laboratory of Fluorescence Dynamics, Department of Biomedical EngineeringUniversity of California IrvineIrvineUSA
  3. 3.MIND Institute, Center for Neurobiology of Learning and MemoryUniversity of CaliforniaIrvineUSA

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