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nuupeptide

Overlooked biology: NAD+ and MOTS-c

References for nuupeptide

The source list for the exhibits: chemistry, experimental tissue, human trials and observational cohorts.

Opening selections

The cardiac ketone-making paper supplies the opening exhibit. For the broader NAD+ picture, the review of metabolism during aging explains the chemistry, while the 2025 assessment of human precursor trials describes the clinical limitations. Reading those together prevents the elegance of a mechanism from doing the work of an outcome study.

For MOTS-c, the 2023 review of stress, metabolism and aging gives the wider context. I would then spend time with the CK2 tissue experiments and the human hemodialysis cohort. They ask markedly different questions about the same peptide.

Complete source list

The entries below retain the publication details, identifiers and source links for all the studies used here. The list includes precursor interventions in people, mouse experiments, cell work and reviews. The heart paper’s human myocardium component and the MOTS-c cohort’s human participants deserve particular care: tissue experiments and observational follow-up each answer a narrower question than a clinical treatment trial.

Sources

  1. Vinten KT, Trętowicz MM, Coskun E, van Weeghel M, Cantó C, Zapata-Pérez R, Janssens GE, Houtkooper RH. NAD(+) precursor supplementation in human ageing: clinical evidence and challenges. Nat Metab. 2025;7:1974-1990. ↗
  2. Yi L, Maier AB, Tao R, Lin Z, Vaidya A, Pendse S, Thasma S, Andhalkar N, Avhad G, Kumbhar V. The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. GeroScience 2023. 2023;45:29-43. ↗
  3. Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, Mills KF, Sindelar M, Pietka T, Patterson BW, Imai SI, Klein S. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372:1224-1229. ↗
  4. Covarrubias AJ, et al. NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol. 2021. ↗
  5. Conze D, Brenner C, Kruger CL. Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Sci Rep. 2019;9:9772. ↗
  6. Camacho-Pereira J, Tarragó MG, Chini CCS, 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;23:1127-1139. ↗
  7. Koay YC, McIntosh B, Ng YH, et al. The Heart Has Intrinsic Ketogenic Capacity that Mediates NAD(+) Therapy in HFpEF. Circulation Research. 2025;136:1113-1130. ↗
  8. Kumagai H, Kim SJ, Miller B, et al. MOTS-c modulates skeletal muscle function by directly binding and activating CK2. iScience. 2024;27(11):111212. ↗
  9. Bolignano D, Greco M, Presta P, Duni A, et al. The Mitochondrial-Derived Peptide MOTS-c May Refine Mortality and Cardiovascular Risk Prediction in Chronic Hemodialysis Patients: A Multicenter Cohort Study. Blood Purification. 2024;53(10):824-837. ↗
  10. Wan W, Zhang L, Lin Y, Rao X, Wang X, Hua F, Ying J. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. Journal of Translational Medicine. 2023;21(1):36. ↗
  11. Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, Lu R, Cohen P, Graham NA, Benayoun BA, Merry TL, Lee C. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications. 2021;12(1):470. ↗
  12. Kim KH, Son JM, Benayoun BA, Lee C. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metabolism. 2018;28(3):516-524.e7. ↗