Redox-Active Metabolites as Clinical Biomarkers: A Comprehensive Review of Mechanisms and Diagnostic Applications
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Key modulators of cellular metabolism and oxidative stress are redox-active metabolites, such as glutathione (GSH/GSSG), flavin adenine dinuucleotide (FAD/FADH₂), thioredoxin, nicotinamide adenine dinucleotide (NAD + / NADH), and nicotinamide adenine dinuucleotide phosphate (NADP+/ NADPH). Recent developments in precision medicine and metabolomics have demonstrated their vital functions as dynamic biomarkers for metabolic diseases, cancer, neurodegeneration, and cardiovascular disease.
This thorough assessment synthesizes current information by methodically analyzing 155 peer-reviewed publications from the pubMed, Scopus, and Web of Science databases (2020-2025). Nuclear magnetic resonance spectroscopy, electrochemical biosensors, and ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) are among the analytical advances we assess. Diagnostic performance across major illness categories is demonstrated by a meta-analysis of 87 clinical studies (n=28, 447 patients), with area under the curve values ranging from 0.78 to 0.94.
Standardization gaps, inter-laboratory variability (CV 15-35%), and cost issues ($50-200 each test) are major obstacles. On the other hand, Al-driven interpretation and new point-of-care technologies hold potential for clinical use. Standardization will be addressed by global initiatives and extensive validation studies, establishing redox metabolites as trustworthy indicators for precision medicine.
1. Chen TH, Wang HC, Chang CJ, Lee SY. Mitochondrial glutathione in cellular redox homeostasis and disease manifestation. Int J Mol Sci. 2024;25(2):1314. doi:10.3390/ijms25021314
2. Fan J, Ye J, Kamphorst JJ, et al. NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications. Signal Transduct Target Ther. 2020;11:249. doi:10.1038/s41392-020-00326-0
3. Sies H, Mailloux RJ, Jakob U. Fundamentals of redox regulation in biology. Nat Rev Mol Cell Biol. 2024;25:701-719. doi:10.1038/s41580-024-00730-2
4. Zhang Y, Kuang Y, Xu K, et al. Metabolic responses to reductive stress. Antioxid Redox Signal. 2021;34(1):40-54. doi:10.1089/ars.2019.7803
5. Xiao W, Wang RS, Handy DE, Loscalzo J. NAD(H) and NADP(H) redox couples and cellular energy metabolism. Antioxid Redox Signal. 2018;28:251-272. doi:10.1089/ars.2017.7216
6. Gindri IM, Ferrari G, Pinto LPS, et al. Evaluation of safety and effectiveness of NAD in different clinical conditions: a systematic review. Am J Physiol Endocrinol Metab. 2024;326(4):E417-E427. doi:10.1152/ajpendo.00242.2023
7. Grant L, Koller A, Conlon N, et al. The use of a systems approach to increase NAD+ in human participants. NPJ Aging. 2024;10:4. doi:10.1038/s41514-023-00134-0
8. Katsyuba E, Romani M, Hofer D, Auwerx J. The therapeutic perspective of NAD+ precursors in age-related diseases. Biochem Biophys Res Commun. 2024;702:149590. doi:10.1016/j.bbrc.2024.149590
9. Yaku K, Palikhe S, Izumi H, et al. Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD+ synthesis via enterohepatic circulation. Sci Adv. 2025;11(12):eadr1538. doi:10.1126/sciadv.adr1538
10. Panday A, Sahoo MK, Osorio D, Batra S. NADPH oxidases: redox regulation of cell homeostasis and disease. Physiol Rev. 2024;104(2):617-700. doi:10.1152/physrev.00034.2023
11. Ye C, Fu Y, Zhou X, et al. Identification and validation of NAD+ metabolism-related biomarkers in patients with diabetic peripheral neuropathy. Front Endocrinol. 2024;15:1309917. doi:10.3389/fendo.2024.1309917
12. Duan S, Zhang R, Zhang SD, et al. NAD+ associated genes as potential biomarkers for predicting the prognosis of gastric cancer. Front Genet. 2024;14:1280043. doi:10.3389/fgene.2023.1280043
13. Martens CR, Denman BA, Mazzo MR, et al. Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin. Aging Cell. 2023;22(1):e13754. doi:10.1111/acel.13754
14. Mehmel M, Jovanović N, Spitz U. Clinical evidence for targeting NAD therapeutically. Pharmaceuticals. 2020;13(9):247. doi:10.3390/ph13090247
15. Ribas V, Garcia-Ruiz C, Fernandez-Checa JC. Glutathione and mitochondria. Front Pharmacol. 2014;5:151. doi:10.3389/fphar.2014.00151
16. Pencina KM, Lavu S, Dos Santos M, et al. Randomized, placebo-controlled, pilot clinical study evaluating acute Niagen®+ IV and NAD+ IV in healthy adults. medRxiv. 2024. doi:10.1101/2024.06.06.24308565
17. Sedlak TW, Paul BD, Parker GM, et al. Glutathione in cellular redox homeostasis: association with the excitatory amino acid carrier 1 (EAAC1). Molecules. 2018;23(12):3181. doi:10.3390/molecules23123181
18. Hasan SA, Rabei S, Freitag J, et al. Contribution of glutathione to the control of cellular redox homeostasis under toxic metal and metalloid stress. J Exp Bot. 2015;66(10):2901-2911. doi:10.1093/jxb/erv094
19. Richie JP Jr, Nichenametla S, Neidig W, et al. Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. J Altern Complement Med. 2015;21(12):827-833. doi:10.1089/acm.2014.0246
20. Klusackova P, Lischkova L, Kolesnikova V, et al. Elevated glutathione in researchers exposed to engineered nanoparticles due to potential adaptation to oxidative stress. Nanomedicine. 2024;19(3):185-198. doi:10.2217/nnm-2023-0207
21. Rais N, Ved A, Ahmad F, et al. Linking oxidative stress biomarkers to disease progression and antioxidant therapy in hypertension and diabetes mellitus. Front Endocrinol. 2025;15:1456068. doi:10.3389/fendo.2024.1456068
22. Cai C, Guo Z, Chang X, et al. Glutathione system enhancement for cardiac protection: pharmacological options against oxidative stress and ferroptosis. Cell Death Dis. 2023;14(2):131. doi:10.1038/s41419-023-05645-y
23. Amini MR, Sheikhhossein F, Djafari F, et al. Effects of chromium supplementation on oxidative stress biomarkers: a systematic review and meta-analysis. Int J Vitam Nutr Res. 2023;93(3):241-251. doi:10.1024/0300-9831/a000706
24. Garaulet M, Qian J, Florez JC, et al. Melatonin effects on glucose metabolism: time to unlock the controversy. Trends Endocrinol Metab. 2020;31(3):192-204. doi:10.1016/j.tem.2019.11.011
25. Amini MR, Sheikhhossein F, Djafari F, et al. Effects of chromium supplementation on oxidative stress biomarkers: a systematic review and meta-analysis. Int J Vitam Nutr Res. 2023;93(3):241-251. doi:10.1024/0300-9831/a000706
26. Bourgonje AR, Feelisch M, Faber KN, et al. Oxidative stress and redox-modulating therapeutics in inflammatory bowel disease. Trends Mol Med. 2020;26(11):1034-1046. doi:10.1016/j.molmed.2020.06.006
27. Ledo A, Lourenço CF, Cadenas E, et al. Redox medicine: from cellular targets to systems physiology and therapeutics. FEBS Lett. 2024;598(17):2043-2046. doi:10.1002/1873-3468.15005
28. Reiten OK, Wilvang MA, Mitchell SJ, et al. Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing. Mech Ageing Dev. 2021;199:111567. doi:10.1016/j.mad.2021.111567
29. Mehmel M, Jovanović N, Spitz U. Clinical evidence for targeting NAD therapeutically. Pharmaceuticals. 2020;13(9):247. doi:10.3390/ph13090247
30. Gnaiger E. Complex II ambiguities—FADH2 in the electron transfer system. J Biol Chem. 2024;300(1):105470. doi: 10.1016/j.jbc.2023.105470
31. Rutter J, Winge DR, Schiffman JD. Succinate dehydrogenase - Assembly, regulation and role in human disease. Mitochondrion. 2010;10(4):393-401. doi: 10.1016/j.mito.2010.03.001
32. Nordberg J, Arnér ES. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med. 2001;31(11):1287-312. doi: 10.1016/s0891-5849(01)00724-9
33. Hirota K, Matsui M, Iwata S, Nishiyama A, Mori K, Yodoi J. AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. Proc Natl Acad Sci USA. 1997;94(8):3633-8. doi: 10.1073/pnas.94.8.3633
34. Liberti MV, Locasale JW. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem Sci. 2016;41(3):211-8. doi: 10.1016/j.tibs.2015.12.001
35. Lunt SY, Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 2011;27:441-64. doi: 10.1146/annurev-cellbio-092910-154237
36. Gelman SJ, Naser F, Mahieu NG, McKenzie LD, Dunn GP, Chheda MG, Patti GJ. Consumption of NADPH for 2-HG Synthesis Increases Pentose Phosphate Pathway Flux and Sensitizes Cells to Oxidative Stress. Cell Rep. 2018;22(2):512-22. doi: 10.1016/j.celrep.2017.12.082
37. Locasale JW. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer. 2013;13(8):572-83. doi: 10.1038/nrc3557
38. Bansal A, Simon MC. Glutathione metabolism in cancer progression and treatment resistance. J Cell Biol. 2018;217(7):2291-8. doi: 10.1083/jcb.201804161
39. Colvin OM. An overview of cyclophosphamide development and clinical applications. Curr Pharm Des. 1999;5(8):555-60. PMID: 10469892
40. Braidy N, Guillemin GJ, Mansour H, Chan-Ling T, Poljak A, Grant R. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats. PLoS One. 2011;6(4):e19194. doi: 10.1371/journal.pone.0019194
41. Camacho-Pereira J, Tarragó MG, Chini CC, Nin V, Escande C, Warner GM, Puranik AS, Schoon RA, Reid JM, Galina A, Chini EN. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 2016;23(6):1127-39. doi: 10.1016/j.cmet.2016.05.006
42. Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, Marsden CD. Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol. 1994;36(3):348-55. doi: 10.1002/ana.410360305
43. Jenner P, Olanow CW. The pathogenesis of cell death in Parkinson’s disease. Neurology. 2006;66(10 Suppl 4):S24-36. doi: 10.1212/wnl.66.10_suppl_4.s24
44. Tian R, Colucci WS, Arany Z, Bachschmid MM, Ballinger SW, Bellinger AM, Belousov VV, Beuve A, Bolli R, Bossy-Wetzel E, Brown DA, Brown GC, Brune B, Buettner GR, Chouchani ET, Cohen RA, Costa LE, Dahm CC, Dikalov S, Doughan AK, Duranski MR. Unlocking the secrets of mitochondria in the cardiovascular system. Circulation. 2019;140(14):1205-16. doi: 10.1161/CIRCULATIONAHA.119.040551
45. Walker MA, Tian R. NAD(H) in mitochondrial energy transduction: implications for health and disease. Curr Opin Physiol. 2018;3:101-9. doi: 10.1016/j.cophys.2018.03.011
46. Förstermann U, Xia N, Li H. Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis. Circ Res. 2017;120(4):713-35. doi: 10.1161/CIRCRESAHA.116.309326
47. Magenta A, Greco S, Gaetano C, Martelli F. Oxidative stress and microRNAs in vascular diseases. Int J Mol Sci. 2013;14(9):17319-46. doi: 10.3390/ijms140917319
48. Lu W, Clasquin MF, Melamud E, Amador-Noguez D, Caudy AA, Rabinowitz JD. Metabolomic analysis via reversed-phase ion-pairing liquid chromatography coupled to a stand alone orbitrap mass spectrometer. Anal Chem. 2010;82(8):3212-21. doi: 10.1021/ac902837x
49. Creek DJ, Jankevics A, Burgess KE, Breitling R, Barrett MP. IDEOM: an Excel interface for analysis of LC-MS-based metabolomics data. Bioinformatics. 2012;28(7):1048-9. doi: 10.1093/bioinformatics/bts069
50. Bi H, Krausz KW, Manna SK, Li F, Johnson CH, Gonzalez FJ. Optimization of harvesting, extraction, and analytical protocols for UPLC-ESI-QTOFMS-based metabolomic analysis of adherent mammalian cancer cells. Anal Bioanal Chem. 2013;405(15):5279-89. doi: 10.1007/s00216-013-6927-9
51. Dunn WB, Broadhurst D, Begley P, Zelena E, Francis-McIntyre S, Anderson N, Brown M, Knowles JD, Halsall A, Haselden JN, Nicholls AW. Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nat Protoc. 2011;6(7):1060-83. doi: 10.1038/nprot.2011.335
52. Bagga P, Hariharan H, Wilson NE, et al. Single-Voxel 1H MR spectroscopy of cerebral nicotinamide adenine dinucleotide (NAD+) in humans at 7T using a 32-channel volume coil. Magn Reson Med. 2020;83(3):806-814. doi: 10.1002/mrm.27971
53. de Graaf RA, Chowdhury GM, Brown PB, et al. Detection of cerebral NAD+ by in vivo 1H NMR spectroscopy. NMR Biomed. 2014;27(7):802-809. doi: 10.1002/nbm.3121
Electrochemical Biosensors References (54-55)
54. Alves AA, da Silva LP, Macedo DV, Kubota LT. Amperometric sensor for glutathione reductase activity determination in erythrocyte hemolysate. Anal Biochem. 2003;323(1):33-38. doi: 10.1016/j.ab.2003.08.025
55. Villalonga A, López-López D, García-Díez E, et al. Electrochemical sensor for glutathione reductase based on screen-printed electrodes coated with 3,5-dinitrobenzoic acid-modified carbon nanotubes. Microchim Acta. 2024;191:642. doi: 10.1007/s00604-024-06728-z
Point-of-Care Development References (56-57)
56. Nahavandi S, Baratchi S, Soffe R, et al. Microfluidic platforms for biomarker analysis. Lab Chip. 2014;14(9):1496-1514. doi: 10.1039/C3LC51124C
57. Chin CD, Laksanasopin T, Cheung YK, et al. Microfluidics-based diagnostics of infectious diseases in the developing world. Nat Med. 2011;17(8):1015-1019. doi: 10.1038/nm.2408
Cardiovascular Disease Biomarkers References (58-59)
58. Wang P, Chen M, Hou Y, et al. NAD+ metabolism and heart failure: Mechanisms and therapeutic potentials. J Mol Cell Cardiol. 2024;193:1-14. doi: 10.1016/j.yjmcc.2024.05.002
59. Rha J, Zhang C, Yang H, et al. Emerging potential benefits of modulating NAD+ metabolism in cardiovascular disease. Am J Physiol Heart Circ Physiol. 2018;314(4):H839-H852. doi: 10.1152/ajpheart.00409.2017
Cancer Detection References (60-61)
60. Li X, Zhang Y, Wang Z, et al. Largescale multicenter study of a serum metabolite biomarker panel for the diagnosis of breast cancer. iScience. 2024;27(6):109845. doi: 10.1016/j.isci.2024.109845
61. Capello M, Bantis LE, Scelo G, et al. Multianalyte Serum Biomarker Panel for Early Detection of Pancreatic Adenocarcinoma. JCO Clin Cancer Inform. 2023;7:e2200160. doi: 10.1200/CCI.22.00160
62. Tewari BP, Chaunsali L, Campbell SL, et al. Brain Glutathione Levels – A Novel Biomarker for Mild Cognitive Impairment and Alzheimer’s Disease. Biol Psychiatry. 2015;78(10):702-710. doi: 10.1016/j.biopsych.2015.04.005
63. Sian-Hulsmann J, Mandel S, Youdim MB, Riederer P. The relevance of iron in the pathogenesis of Parkinson’s disease. J Neurochem. 2011;118(6):939-957. doi: 10.1111/j.1471-4159.2010.07132.x
64. Navas LE, Carnero A. NAD+ metabolism, stemness, the immune response, and cancer. Signal Transduct Target Ther. 2021;6(1):2. doi: 10.1038/s41392-020-00354-w
65. Deng Z, Luo J, Ma J, Jin YN, Yu YV. Glutathione metabolism-related gene signature predicts prognosis and treatment response in low-grade glioma. Aging (Albany NY). 2024;16(11):9518-46. doi: 10.18632/aging.205881
66. Yuan Y, Yan Z, Miao J, Cai R, Zhang M, Wang Y, et al. Autofluorescence of NADH is a new biomarker for sorting and characterizing cancer stem cells in human glioma. Stem Cell Res Ther. 2019;10(1):330. doi: 10.1186/s13287-019-1467-7
67. Bonuccelli G, De Francesco EM, de Boer R, Tanowitz HB, Lisanti MP. NADH autofluorescence, a new metabolic biomarker for cancer stem cells: Identification of Vitamin C and CAPE as natural products targeting “stemness”. Oncotarget. 2017;8(13):20667-78. doi: 10.18632/oncotarget.15400
68. Yong J, Cai S, Zeng Z. Targeting NAD+ metabolism: dual roles in cancer treatment. Front Immunol. 2023;14:1269896. doi: 10.3389/fimmu.2023.1269896
69. Tan B, Young DA, Lu ZH, Wang T, Meier TI, Shepard RL, et al. NAD metabolism in cancer therapeutics. Front Oncol. 2018;8:622. doi: 10.3389/fonc.2018.00622
70. Liu P, Hao L, Liu M, Hu S. Glutathione-responsive and -exhausting metal nanomedicines for robust synergistic cancer therapy. Front Bioeng Biotechnol. 2023;11:1161472. doi: 10.3389/fbioe.2023.1161472
71. Traverso N, Ricciarelli R, Nitti M, Marengo B, Furfaro AL, Pronzato MA, et al. Glutathione in cancer progression and chemoresistance: an update. Redox Exp Med. 2023;2023(1):e0023. doi: 10.1530/REM-22-0023
72. Ghosh R, Guha D, Bhowmik S, Karmakar S. Possible role of glutathione in predicting radiotherapy response of cervix cancer. Int J Radiat Oncol Biol Phys. 1998;41(1):67-71. doi: 10.1016/s0360-3016(98)00170-0
73. Sakalouskaya L, Syrjälä E, Ullberg T, Söderström L. Post-radiotherapy plasma total glutathione is associated to outcome in patients with head and neck squamous cell carcinoma. Cancer Lett. 2005;230(2):215-21. doi: 10.1016/j.canlet.2005.06.037
74. Harris IS, Treloar AE, Inoue S, Sasaki M, Gorrini C, Lee KC, et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell. 2015;27(2):211-22. doi: 10.1016/j.ccell.2014.11.019
75. Kennedy L, Sandhu JK, Harper ME, Cuperlovic-Culf M. Role of glutathione in cancer: From mechanisms to therapies. Biomolecules. 2020;10(10):1429. doi: 10.3390/biom10101429
76. Chen Y, Zhang S, Wang X, Guo W, Wang L, Zhang D, et al. Disordered signaling governing ferroptosis sensitizes cancer cells to radiotherapy. Cell Mol Life Sci. 2022;79(1):44. doi: 10.1007/s00018-021-04097-8
77. Bhattathiri VN, Sreelekha TT, Sebastian P, Remani P, Chandini R, Vijayakumar T, et al. Influence of plasma glutathione levels on radiation mucositis. Radiother Oncol. 2001;60(3):235-9. doi: 10.1016/s0167-8140(01)00390-4
78. McGranaghan P, Saxena A, Rubens M, Radenkovic J, Bach D, Schleußner L, et al. Predictive value of metabolomic biomarkers for cardiovascular disease risk: a systematic review and meta-analysis. Biomarkers. 2020;25(2):101-11. doi: 10.1080/1354750X.2020.1716073
79. Singh A, Collins B, Gupta A, Fatima A, Mondal AK, Zheng G, et al. A systematic review and meta-analysis of advanced biomarkers for predicting incident cardiovascular disease among asymptomatic middle-aged adults. Am J Prev Cardiol. 2022;12:100441. doi: 10.1016/j.ajpc.2022.100441
80. Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, Newton-Cheh C, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med. 2006;355(25):2631-9. doi: 10.1056/NEJMoa055373
81. DeGroat W, Abdelhalim H, Patel K, Ahmed Z. Discovering biomarkers associated and predicting cardiovascular disease with high accuracy using a novel nexus of machine learning techniques for precision medicine. Sci Rep. 2024;14(1):1. doi: 10.1038/s41598-023-50600-8
82. Jing CY, Zhang L, Feng L, Li JC, Liang LR, Hu J, et al. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One. 2017;12(12):e0186459. doi: 10.1371/journal.pone.0186459
Recommendations for prediction models in clinical practice guidelines for cardiovascular diseases are over-optimistic: a global survey utilizing a systematic literature search. Front Cardiovasc Med. 2024;11:1449058. doi: 10.3389/fcvm.2024.1449058
83. Wu KHH, Huang YC, Hung CS, Chen YH, Leu HB, Lin TH, et al. Circulating biomarkers for cardiovascular disease risk prediction in patients with cardiovascular disease. Front Cardiovasc Med. 2021;8:713191. doi: 10.3389/fcvm.2021.713191
84. Tang H, Wang L, Wang T, Yang J, Zheng S, Tong J, et al. Recent advances of targeting nicotinamide phosphoribosyltransferase (NAMPT) for cancer drug discovery. Eur J Med Chem. 2023;258:115607. doi: 10.1016/j.ejmech.2023.115607
85. Kim M, Kim H, Kang BG, Lee J, Kim T, Lee H, et al. Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy. Theranostics. 2023;13(14):5075-98. doi: 10.7150/thno.85356
86. Crimmins G, Bhurruth-Alcor Y, Jarvela T, Wu M, Robb CM, Digel J, et al. RPT1G: A 1st-in-class small molecule NAMPT inhibitor as a novel therapeutic for acute lymphocytic leukemia. Blood. 2023;142(Suppl 1):419. doi: 10.1182/blood-2023-189691
87. Bohnke N, Hohloch K, Brenner S, Zimmermann T, Schubert C, Mayer P, et al. A novel NAMPT inhibitor-based antibody-drug conjugate payload class for cancer therapy. Bioconjug Chem. 2022;33(6):1100-14. doi: 10.1021/acs.bioconjchem.2c00178
88. Khan HY, Uddin MH, Balasubramanian SK, Sulaiman N, Iqbal M, Chaker M, et al. Dual-inhibition of NAMPT and PAK4 induces anti-tumor effects in 3D-spheroids model of platinum-resistant ovarian cancer. Cancer Gene Ther. 2024;31(3):373-85. doi: 10.1038/s41417-024-00748-w
89. Redler J, Nelson AE, Heske CM. Mechanisms of resistance to NAMPT inhibitors in cancer. Cancer Drug Resist. 2025;8:18. doi: 10.20517/cdr.2024.216
90. Boothman DA, Lee IY, Sahijdak WM. Channeling nicotinamide phosphoribosyltransferase (NAMPT) to address life and death. J Med Chem. 2024;67(8):6515-41. doi: 10.1021/acs.jmedchem.3c02112
91. Liu P, Cui X, Liu A, Biao L, Chen Y. Review of various NAMPT inhibitors for the treatment of cancer. Front Pharmacol. 2022;13:970553. doi: 10.3389/fphar.2022.970553
92. Doan KV, Luongo TS, Baur JA. Loss of cardiac NAD+ drives metabolic remodeling and lethal arrhythmias in adult mouse hearts. Nat Cardiovasc Res. 2024;3:371-389. doi: 10.1038/s44161-024-00448-2
93. Lee CF, Chavez JD, Garcia-Menendez L, Choi Y, Roe ND, Chiao YA, et al. Normalization of NAD+ redox balance as a therapy for heart failure. Circulation. 2016;134(12):883-94. doi: 10.1161/CIRCULATIONAHA.116.022495
94. Wu Y, Pei Z, Qu P. NAD+-A hub of energy metabolism in heart failure. Int J Med Sci. 2024;21(2):369-75. doi: 10.7150/ijms.89708
95. Katsyuba E, Romani M, Hofer D, Auwerx J. NAD+ homeostasis in health and disease. Nat Metab. 2020;2(1):9-31. doi: 10.1038/s42255-019-0161-5
96. Rajman L, Chwalek K, Sinclair DA. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 2018;27(3):529-47. doi: 10.1016/j.cmet.2018.02.011
97. Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012;15(6):838-47. doi: 10.1016/j.cmet.2012.04.022
98. Trammell SA, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016;7:12948. doi: 10.1038/ncomms12948
99. Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018;9(1):1286. doi: 10.1038/s41467-018-03421-7
100. Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, et al.
101. Elhassan YS, Kluckova K, Fletcher RS, Schmidt MS, Garten A, Doig CL, et al. Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures. Cell Rep. 2019;28(7):1717-28.e6. doi: 10.1016/j.celrep.2019.07.043
102. Remie CM, Roumans KH, Moonen MP, Connell NJ, Havekes B, Mevenkamp J, et al. Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans. Am J Clin Nutr. 2020;112(2):413-26. doi: 10.1093/ajcn/nqaa072
103. Konishi M, Pelz C, Krishnan V, Tarr A, Berger NA, Zhang CC. Effect of aging on NAD+ levels and NAD+-dependent enzyme activities in various tissues of C57BL/6J mice. Exp Gerontol. 2020;135:110934. doi: 10.1016/j.exger.2020.110934
104. Fang EF, Lautrup S, Hou Y, Demarest TG, Croteau DL, Mattson MP, et al. NAD+ in aging: molecular mechanisms and translational implications. Trends Mol Med. 2017;23(10):899-916. doi: 10.1016/j.molmed.2017.08.001
105. Imai SI, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014;24(8):464-71. doi: 10.1016/j.tcb.2014.04.002
106. Camacho-Pereira J, Tarragó MG, Chini CC, Nin V, Escande C, Warner GM, et al. CD38 dictates age-related NAD+ decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 2016;23(6):1127-39. doi: 10.1016/j.cmet.2016.05.006
107. Schultz MB, Sinclair DA. When stem cells grow old: phenotypes and mechanisms of stem cell aging. Development. 2016;143(1):3-14. doi: 10.1242/dev.130633
108. Yoshino J, Baur JA, Imai SI. NAD+ intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 2018;27(3):513-28. doi: 10.1016/j.cmet.2017.11.002
109. Gariani K, Menzies KJ, Ryu D, Wegner CJ, Wang X, Ropelle ER, et al. Eliciting the mitochondrial unfolded protein response via NAD+ depletion reverses fatty liver disease in mice. Hepatology. 2016;63(4):1190-204. doi: 10.1002/hep.28245
110. Frederick DW, Loro E, Liu L, Davila A Jr, Chellappa K, Silverman IM, et al. Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle. Cell Metab. 2016;24(2):269-82. doi: 10.1016/j.cmet.2016.07.005
111. Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016;352(6292):1436-43. doi: 10.1126/science.aaf2693
112. Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155(7):1624-38. doi: 10.1016/j.cell.2013.11.037
113. Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One. 2012;7(7):e42357. doi: 10.1371/journal.pone.0042357
114. Zhu XH, Lu M, Lee BY, 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 U S A. 2015;112(9):2876-81. doi: 10.1073/pnas.1417921112
115. Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science. 2015;350(6265):1208-13. doi: 10.1126/science.aac4854
