Tracing the Metabolic Flux of Orally Administered NAD+ Precursors

Summary

We are doing this research to learn how healthy younger and older adults use two forms of vitamin B3-called nicotinamide mononucleotide (NMN) and nicotinamide (NAM)-to make NAD+. NAD+ is a natural substance that cells need for energy and other important processes. Our goal is to find out how these NAD precursors are absorbed and metabolized and how they raise NAD+ in different tissues. Who can join? Healthy adults men and women aged 18 to 40 (younger group) or 65 and older (older group) Participants with a body mass index ranging between 19 and 35 No major health issues like diabetes or severe kidney disease What will happen? Participants will take labeled or unlabeled NMN or NAM by mouth every day for 14 days. Researchers will collect blood, urine, and stool samples. Researchers also do a small muscle biopsy (under local numbing) twice to check how these NAD precursors raise NAD+ in muscle. Why is this important? NAD+ levels may drop as people age, and this drop could affect overall health and energy in cells. A better understanding of how NMN and NAM are metabolized in the body to raise NAD+ levels in both younger and older adults may help us optimize dosing and strategies for raising NAD in older people. Possible benefits and risks: Participants may not get any direct health benefit from this study; the main goal is to gather new knowledge. NMN and NAM appear safe in the doses used. A muscle biopsy may cause soreness or bruising. Researchers will monitor participants closely for any side effects throughout the study.

Timeline

Start

2025-04-28

Primary completion

2026-12

Completion

2027-06

Publications

• Background Sauve AA, Wang Q, Zhang N, Kang S, Rathmann A, Yang Y. Triple-Isotope Tracing for Pathway Discernment of NMN-Induced NAD+ Biosynthesis in Whole Mice. Int J Mol Sci. 2023 Jul 5;24(13):11114. doi: 10.3390/ijms241311114.
• Background Amjad S, Nisar S, Bhat AA, Shah AR, Frenneaux MP, Fakhro K, Haris M, Reddy R, Patay Z, Baur J, Bagga P. Role of NAD+ in regulating cellular and metabolic signaling pathways. Mol Metab. 2021 Jul;49:101195. doi: 10.1016/j.molmet.2021.101195. Epub 2021 Feb 17.
• Background Pencina KM, Lavu S, Dos Santos M, Beleva YM, Cheng M, Livingston D, Bhasin S. MIB-626, an Oral Formulation of a Microcrystalline Unique Polymorph of beta-Nicotinamide Mononucleotide, Increases Circulating Nicotinamide Adenine Dinucleotide and its Metabolome in Middle-Aged and Older Adults. J Gerontol A Biol Sci Med Sci. 2023 Jan 26;78(1):90-96. doi: 10.1093/gerona/glac049.
• Background Pencina KM, Valderrabano R, Wipper B, Orkaby AR, Reid KF, Storer T, Lin AP, Merugumala S, Wilson L, Latham N, Ghattas-Puylara C, Ozimek NE, Cheng M, Bhargava A, Memish-Beleva Y, Lawney B, Lavu S, Swain PM, Apte RS, Sinclair DA, Livingston D, Bhasin S. Nicotinamide Adenine Dinucleotide Augmentation in Overweight or Obese Middle-Aged and Older Adults: A Physiologic Study. J Clin Endocrinol Metab. 2023 Jul 14;108(8):1968-1980. doi: 10.1210/clinem/dgad027.
• Background Dutta T, Kapoor N, Mathew M, Chakraborty SS, Ward NP, Prieto-Farigua N, Falzone A, DeLany JP, Smith SR, Coen PM, DeNicola GM, Gardell SJ. Source of nicotinamide governs its metabolic fate in cultured cells, mice, and humans. Cell Rep. 2023 Mar 28;42(3):112218. doi: 10.1016/j.celrep.2023.112218. Epub 2023 Mar 9.
• Background Kim LJ, Chalmers TJ, Madawala R, Smith GC, Li C, Das A, Poon EWK, Wang J, Tucker SP, Sinclair DA, Quek LE, Wu LE. Host-microbiome interactions in nicotinamide mononucleotide (NMN) deamidation. FEBS Lett. 2023 Sep;597(17):2196-2220. doi: 10.1002/1873-3468.14698. Epub 2023 Aug 9.
• Background Xiao W, Wang RS, Handy DE, Loscalzo J. NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism. Antioxid Redox Signal. 2018 Jan 20;28(3):251-272. doi: 10.1089/ars.2017.7216. Epub 2017 Jul 28.
• Background Chellappa K, McReynolds MR, Lu W, Zeng X, Makarov M, Hayat F, Mukherjee S, Bhat YR, Lingala SR, Shima RT, Descamps HC, Cox T, Ji L, Jankowski C, Chu Q, Davidson SM, Thaiss CA, Migaud ME, Rabinowitz JD, Baur JA. NAD precursors cycle between host tissues and the gut microbiome. Cell Metab. 2022 Dec 6;34(12):1947-1959.e5. doi: 10.1016/j.cmet.2022.11.004.
• Background Bhasin S, Seals D, Migaud M, Musi N, Baur JA. Nicotinamide Adenine Dinucleotide in Aging Biology: Potential Applications and Many Unknowns. Endocr Rev. 2023 Nov 9;44(6):1047-1073. doi: 10.1210/endrev/bnad019.

Drugs

Indications

No indication recorded.