Dietary Nucleotides Enhance Neurogenesis, Cognitive Capacity, Muscle Function, and Body Composition in Older Adults: A Randomized, Triple-Blind, Controlled Clinical Trial

  1. Gené Morales, Javier 12
  2. Juesas Torres, Álvaro 23
  3. Saez Berlanga, Ángel 12
  4. Martin, Ezequiel G. 2
  5. Garrigues-Pelufo, Luis 2
  6. Sandoval-Camargo, Brayan S. 2
  7. Martin-Rivera, Fernando 12
  8. Chulvi Medrano, Iván 12
  9. Jiménez Martínez, Pablo 25
  10. Alix Fages, Carlos 25
  11. Gargallo Bayo, Pedro 2
  12. Fernández Garrido, Julio Jorge 4
  13. Caballero Luna, Oscar 4
  14. Jerez Martinez, Agustín 56
  15. Colado Sánchez, Juan Carlos 12
  1. 1 Department of Physical Education and Sports, University of Valencia, 46010 Valencia, Spain
  2. 2 Research Group in Prevention and Health in Exercise and Sport (PHES), University of Valencia, 46010 Valencia, Spain
  3. 3 Department of Education Sciences, CEU Cardenal Herrera University, 46115 Castellón, Spain
  4. 4 Nursing Department, Faculty of Nursing and Podiatry, University of Valencia, 46010 Valencia, Spain
  5. 5 ICEN Research Center, Department of Health Research, 38002 Santa Cruz de Tenerife, Spain
  6. 6 Faculty of Sports Sciences, Catholic University of Murcia (UCAM), 30107 Murcia, Spain
Journal:
Nutrients

ISSN: 2072-6643

Year of publication: 2025

Volume: 17

Issue: 9

Pages: 1431

Type: Article

DOI: 10.3390/NU17091431 GOOGLE SCHOLAR lock_openOpen access editor

More publications in: Nutrients

Abstract

Background/Objectives: this study evaluated the differential effects of two dis-tinct dietary nucleotide supplements, combined with spontaneous physical activity, onneuromuscular, cognitive, and metabolic adaptations in older adults. Methods: Sixty-ninephysically independent older adults (aged 60–75 years) were randomly assigned to threegroups: (1) a yeast nucleotides formulation (YN) standardized in a high content of freenucleotides (>40%) rich in all macro and micro nutrients naturally occurring in yeast cell(amino acids, minerals and B-group vitamin); (2) a neuro-based formulation (NF) consistingof a blend of monophosphate nucleotides 5′; or (3) a placebo. Participants maintained theirspontaneous physical activities without structured exercise during a 10-week interven-tion. Assessments included physical function, cognitive performance, body composition,quality of life, and serum biomarkers of oxidative stress, inflammation, and neurogenesis.Results: Both nucleotide-supplemented groups demonstrated significant improvementscompared to placebo in physical performance (p ≤ 0.045), cognitive function (Trail MakingTest B [TMT-B]: p ≤ 0.012), oxidative stress biomarkers (p ≤ 0.048), inflammatory cytokines(p ≤ 0.023 ), and quality-of-life parameters (p ≤ 0.047). Body composition remained sta-ble in supplemented groups, whereas placebo increased fat mass (5.04%) and decreasedmuscle mass (−2.18%). Conclusions: Dietary nucleotide supplementation enhances thebenefits of spontaneous physical activity across all measured variables in older adults,highlighting nucleotides as promising nutritional support for healthy aging. YN exhibiteda trend toward greater inflammatory modulation, whereas NF showed a tendency towardenhanced neurotrophic effects and functional improvements, with a statistically significantimprovement in the Timed Up and Go Test (p = 0.014). These findings underscore thepotential for tailored nucleotide-based interventions to optimize distinct physiologicaldomains in aging populations.

Funding information

Prosol S.r.l. provided reagents for the development of the study; however, they were not involved in data collection or data entry, and there were no restrictions on analysis, writing, or publication. This work was supported by a grant from the Generalitat Valenciana of Spain (Angel Saez-Berlanga’s predoctoral grant CIACIF/2021/189, funded by the European Social Fund).

Funders

Bibliographic References

  • World Health Organization (2025, March 12). Ageing and Health Report. Available online: https://www.who.int/news-room/fact-sheets/detail/ageing-and-health.
  • Chen, (2024), Nat. Commun., 15, pp. 1796, 10.1038/s41467-024-45901-z
  • Wang, K., Wang, X., and Wang, Y. (2024). Factors, mechanisms and improvement methods of muscle strength loss. Front. Cell Dev. Biol., 12.
  • Salthouse, (2012), Annu. Rev. Psychol., 63, pp. 201, 10.1146/annurev-psych-120710-100328
  • Pabla, (2024), Clin. Sci., 138, pp. 863, 10.1042/CS20231197
  • Rodrigues, F., Domingos, C., Monteiro, D., and Morouço, P. (2022). A Review on Aging, Sarcopenia, Falls, and Resistance Training in Community-Dwelling Older Adults. Int. J. Environ. Res. Public Health, 19.
  • Latorre-Román, P.Á., Carmona-Torres, J.M., Cobo-Cuenca, A.I., and Laredo-Aguilera, J.A. (2020). Physical Activity, Ability to Walk, Weight Status, and Multimorbidity Levels in Older Spanish People: The National Health Survey (2009–2017). Int. J. Environ. Res. Public Health, 17.
  • Beck, (2016), Eur. J. Ageing, 13, pp. 209, 10.1007/s10433-016-0376-1
  • Esmail, (2020), J. Bodyw. Mov. Ther., 24, pp. 212, 10.1016/j.jbmt.2019.05.004
  • Varma, (2014), J. Appl. Gerontol., 33, pp. 870, 10.1177/0733464813512896
  • Hayes, G., Pinto, J., Sparks, S.N., Wang, C., Suri, S., and Bulte, D.P. (2022). Vascular smooth muscle cell dysfunction in neurodegeneration. Front. Neurosci., 16.
  • Arosio, B., Calvani, R., Ferri, E., Coelho-Junior, H.J., Carandina, A., Campanelli, F., Ghiglieri, V., Marzetti, E., and Picca, A. (2023). Sarcopenia and Cognitive Decline in Older Adults: Targeting the Muscle–Brain Axis. Nutrients, 15.
  • Comporti, (2008), Free Radic. Biol. Med., 44, pp. 247, 10.1016/j.freeradbiomed.2007.10.004
  • Averill-Bates, D.A. (2023). The antioxidant glutathione. Vitamins and Hormones, Academic Press.
  • Teixeira, (2015), J. Alzheimer’s Dis., 46, pp. 423, 10.3233/JAD-150172
  • Buchman, (2016), Neurology, 86, pp. 735, 10.1212/WNL.0000000000002387
  • Waterhouse, (2009), Mol. Cell. Neurosci., 42, pp. 81, 10.1016/j.mcn.2009.06.009
  • Short, (2005), Proc. Natl. Acad. Sci. USA, 102, pp. 5618, 10.1073/pnas.0501559102
  • Zeng, Z., Centner, C., Gollhofer, A., and König, D. (2021). Effects of Dietary Strategies on Exercise-Induced Oxidative Stress: A Narrative Review of Human Studies. Antioxidants, 10.
  • Supruniuk, E., Górski, J., and Chabowski, A. (2023). Endogenous and Exogenous Antioxidants in Skeletal Muscle Fatigue Development during Exercise. Antioxidants, 12.
  • Chi, (2015), Int. J. Biol. Macromol., 80, pp. 566, 10.1016/j.ijbiomac.2015.06.055
  • Uberti, (2020), J. Food Sci. Nutr. Res., 3, pp. 231, 10.26502/jfsnr.2642-11000052
  • Gil, (2002), Br. J. Nutr., 87, pp. S135, 10.1079/BJN2001467
  • Verkerk, (2011), NHD Clin., 64, pp. 29
  • Dancey, (2006), Nutr. J., 5, pp. 16, 10.1186/1475-2891-5-16
  • Hawkes, (2005), Eur. J. Clin. Nutr., 60, pp. 254, 10.1038/sj.ejcn.1602310
  • Belo, (2006), Gut, 55, pp. 165, 10.1136/gut.2005.076752
  • Jyonouchi, (1994), J. Nutr., 124, pp. 138S, 10.1093/jn/124.suppl_1.138S
  • Koletzko, (2005), J. Pediatr. Gastroenterol. Nutr., 41, pp. 584, 10.1097/01.mpg.0000187817.38836.42
  • Xu, (2013), J. Nutr. Health Aging, 17, pp. 223, 10.1007/s12603-012-0399-z
  • Chen, (2000), J. Nutr., 130, pp. 3085, 10.1093/jn/130.12.3085
  • Cai, X., Bao, L., Wang, N., Xu, M., Mao, R., and Li, Y. (2016). Dietary nucleotides supplementation and liver injury in alcohol-treated rats: A metabolomics investigation. Molecules, 21.
  • Xu, (2013), Int. Immunopharmacol., 17, pp. 50, 10.1016/j.intimp.2013.04.032
  • Ostojic, (2013), Nutrients, 5, pp. 4776, 10.3390/nu5114776
  • Bentley, (2007), J. Sports Med. Phys. Fitness, 47, pp. 112
  • Bentley, (2006), J. Sports Med. Phys. Fitness, 46, pp. 84
  • González-Marenco, R., Estrada-Sánchez, I.A., Medina-Escobedo, M., Chim-Aké, R., and Lugo, R. (2024). The Effect of Oral Adenosine Triphosphate (ATP) Supplementation on Anaerobic Exercise in Healthy Resistance-Trained Individuals: A Systematic Review and Meta-Analysis. Sports, 12.
  • Roberts, (2011), Age Ageing, 40, pp. 423, 10.1093/ageing/afr051
  • Rikli, R., and Jones, J. (2013). Senior Fitness Test Manual, Human Kinetics. [2nd ed.].
  • Reitan, (1958), Percept. Mot. Skills, 8, pp. 271, 10.2466/pms.1958.8.3.271
  • Vilagut, (2008), Med. Clin., 130, pp. 726, 10.1157/13121076
  • Banegas, (2003), Med. Clin., 120, pp. 568, 10.1016/S0025-7753(03)73775-0
  • (2025, March 14). Aecosan-Agencia Española de Consumo, Seguridad Alimentaria y Nutrición. Available online: https://www.aesan.gob.es/AECOSAN/web/noticias_y_actualizaciones/noticias/2018/RD_complementos_alimenticios.htm.
  • Okabe, K., Yaku, K., Uchida, Y., Fukamizu, Y., Sato, T., Sakurai, T., Tobe, K., and Nakagawa, T. (2022). Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects. Front. Nutr., 9.
  • Song, (2023), Adv. Nutr., 14, pp. 1416, 10.1016/j.advnut.2023.08.008
  • Teixeira, (2018), Nutr. Diet., 75, pp. 219, 10.1111/1747-0080.12401
  • Evenepoel, (2020), J. Med. Internet Res., 22, pp. e18237, 10.2196/18237
  • Cleland, C., Ferguson, S., Ellis, G., and Hunter, R.F. (2018). Validity of the International Physical Activity Questionnaire (IPAQ) for assessing moderate-to-vigorous physical activity and sedentary behaviour of older adults in the United Kingdom. BMC Med. Res. Methodol., 18.
  • Kowalski, (2012), Int. J. Behav. Nutr. Phys. Act., 9, pp. 148, 10.1186/1479-5868-9-148
  • Carrera, (2017), Rev. Enfermería Trab., 7, pp. 49
  • Craig, (2003), Med. Sci. Sports Exerc., 35, pp. 1381, 10.1249/01.MSS.0000078924.61453.FB
  • Lin, (2005), J. Occup. Health, 54, pp. 223, 10.1539/joh.11-0225-OA
  • Sanca, (2025), Sports Med. Open, 11, pp. 19, 10.1186/s40798-025-00821-0
  • (2010), Eur. J. Sport Sci., 10, pp. 297, 10.1080/17461390903426667
  • (2007), J. Int. Neuropsychol. Soc., 13, pp. 903
  • Vickers, (2001), BMJ, 323, pp. 1123, 10.1136/bmj.323.7321.1123
  • Corder, G.W., and Foreman, D.I. (2014). Non-Parametric Statistics: A Step-by-Step Approach, Wiley. [2nd ed.].
  • Quade, (1967), J. Am. Stat. Assoc., 62, pp. 1187, 10.1080/01621459.1967.10500925
  • Cohen, J. (1988). Statistical Power Analysis for the Behavioral Sciences, Lawrence Erlbaum Associates. [2nd ed.].
  • Gupta, (2011), Perspect. Clin. Res., 2, pp. 109, 10.4103/2229-3485.83221
  • Farges, (2012), Br. J. Nutr., 108, pp. 2054, 10.1017/S0007114512000177
  • Kahmann, (2008), Rejuvenation Res., 11, pp. 227, 10.1089/rej.2007.0613
  • Clarke, H.E., Akhavan, N.S., Behl, T.A., Ormsbee, M.J., and Hickner, R.C. (2025). Effect of Creatine Monohydrate Supplementation on Macro- and Microvascular Endothelial Function in Older Adults: A Pilot Study. Nutrients, 17.
  • Ryder, (2005), J. Am. Geriatr. Soc., 53, pp. 1875, 10.1111/j.1532-5415.2005.53561.x
  • Gualix, (2016), Neuropharmacology, 104, pp. 243, 10.1016/j.neuropharm.2015.09.002
  • Roy, (2016), Chem. Rev., 116, pp. 7854, 10.1021/acs.chemrev.6b00174
  • Singh, (2024), Cold Spring Harb. Perspect. Med., 14, pp. a041197, 10.1101/cshperspect.a041197
  • Saviano, A., Casillo, G.M., Raucci, F., Pernice, A., Santarcangelo, C., Piccolo, M., Ferraro, M.G., Ciccone, M., Sgherbini, A., and Pedretti, N. (2021). Supplementation with ribonucleotide-based ingredient (Ribodiet®) lessens oxidative stress, brain inflammation, and amyloid pathology in a murine model of Alzheimer. Biomed. Pharmacother., 139.
  • Kujawska, M., Domanskyi, A., and Kreiner, G. (2021). Common Pathways Linking Neurodegenerative Diseases—The Role of Inflammation. Front. Cell Neurosci., 15.
  • Juesas, (2025), Exp. Gerontol., 200, pp. 112683, 10.1016/j.exger.2025.112683