Effects of N -Acetylmannosamine (ManNAc) on Cognitive and Psychological Function in Middle-Aged and Older Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Trial — Oak Academic Publishing
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Effects of N -Acetylmannosamine (ManNAc) on Cognitive and Psychological Function in Middle-Aged and Older Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Trial
Background: To delay the onset of dementia with age, it is important for healthy adults to take preventive measures before cognitive decline occurs. Cognitive function decline is often associated with mood disorders such as depression. N -acetylmannosamine (ManNAc) showed activity in a screening assay for components that induced the generation of orexin-producing neurons. Orexins are neuropeptides involved in the regulation of various bodily functions, such as cognitive and psychological function. Therefore, we aimed to examine the effects of ManNAc intake on cognitive and psychological function in middle-aged and older humans. Methods : A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the impact of ManNAc on cognitive and psychological functions in middle-aged and older healthy participants. Eighty participants were enrolled and randomly divided into active and placebo groups. The participants consumed either food containing ManNAc 8.8 mg or food without ManNAc for 12 weeks. As the main outcome, cognitive function was assessed before and after ingestion using the Cognitrax test. The secondary outcome, psychological function, was also examined using the POMS2. Results: The active group showed statistical significance in the “Neurocognitive Index”, which is an assessment of overall cognitive function, in addition to the “Psychomotor Speed”, “Reaction Time”, “Cognitive Flexibility”, “Executive Function”, and “Motor Speed” factors in the Cognitrax test compared to the placebo group (P < 0.05). Furthermore, the active group showed statistically significant differences in “Vigor-Activity” and “Friendliness” in the POMS2 compared to the placebo group (P < 0.05). No adverse events attributable to the study foods were observed during the study period. Conclusions: Overall, ManNAc improved cognitive and psychological functions in middle-aged and older adults.
Harada, C.N., Natelson Love, M.C. and Triebel, K.L. (2013) Normal Cognitive Aging. Clinics in Geriatric Medicine , 29, 737-752. https://doi.org/10.1016/j.cger.2013.07.002
World Health Organization (2025) Mental Health of Older Adults. https://www.who.int/news-room/fact-sheets/detail/mental-health-of-older-adults
World Health Organization (2025) Dementia. https://www.who.int/news-room/fact-sheets/detail/dementia
Japanese Society of Neurology (2017) Clinical Practice Guideline for Dementia 2017. https://neurology-jp.org/guidelinem/dementia/index.html
Mitchell, A.J. and Shiri‐Feshki, M. (2009) Rate of Progression of Mild Cognitive Impairment to Dementia—Meta‐Analysis of 41 Robust Inception Cohort Studies. Acta Psychiatrica Scandinavica , 119, 252-265. https://doi.org/10.1111/j.1600-0447.2008.01326.x
Manly, J.J., Tang, M., Schupf, N., Stern, Y., Vonsattel, J.G. and Mayeux, R. (2008) Frequency and Course of Mild Cognitive Impairment in a Multiethnic Community. Annals of Neurology , 63, 494-506. https://doi.org/10.1002/ana.21326
Yates, J.A., Clare, L. and Woods, R.T. (2016) What Is the Relationship between Health, Mood, and Mild Cognitive Impairment? Journal of Alzheimer ’ s Disease , 55, 1183-1193. https://doi.org/10.3233/jad-160611
Zhao, J., Liu, Y.W.J., Tyrovolas, S. and Mutz, J. (2023) Exploring the Concept of Psychological Frailty in Older Adults: A Systematic Scoping Review. Journal of Clinical Epidemiology , 159, 300-308. https://doi.org/10.1016/j.jclinepi.2023.05.005
Henry, J.D., Coundouris, S.P., Mead, J., Thompson, B., Hubbard, R.E. and Grainger, S.A. (2022) Social Frailty in Late Adulthood: Social Cognitive and Psychological Well-Being Correlates. The Journals of Gerontology : Series B , 78, 87-96. https://doi.org/10.1093/geronb/gbac157
Rai, H.P. and Mishra, D.N. (2025) Effect of Ashwagandha ( Withania somnifera ) Extract with Sominone (Somin-On™) to Improve Memory in Adults with Mild Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled Study. Journal of Psychop harmacology , 39, 350-363. https://doi.org/10.1177/02698811251324377
Sachs, B.C., Williams, B.J., Gaussoin, S.A., Baker, L.D., Manson, J.E., Espeland, M.A., et al . (2023) Impact of Multivitamin‐Mineral and Cocoa Extract on Incidence of Mild Cognitive Impairment and Dementia: Results from the Cocoa Supplement and Multivitamin Outcomes Study for the Mind (Cosmos‐Mind). Alzheimer ’ s & Dementia , 19, 4863-4871. https://doi.org/10.1002/alz.13078
Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R.M., Tanaka, H., et al . (1998) Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors That Regulate Feeding Behavior. Cell , 92, 573-585. https://doi.org/10.1016/s0092-8674(00)80949-6
de Lecea, L., Kilduff, T.S., Peyron, C., Gao, X.-B., Foye, P.E., Danielson, P.E., et al . (1998) The Hypocretins: Hypothalamus-Specific Peptides with Neuroexcitatory Activity. Proceedings of the National Academy of Sciences , 95, 322-327. https://doi.org/10.1073/pnas.95.1.322
Date, Y., Ueta, Y., Yamashita, H., Yamaguchi, H., Matsukura, S., Kangawa, K., et al . (1999) Orexins, Orexigenic Hypothalamic Peptides, Interact with Autonomic, Neuroendocrine and Neuroregulatory Systems. Proceedings of the National Academy of Scie nces , 96, 748-753. https://doi.org/10.1073/pnas.96.2.748
España, R.A., Reis, K.M., Valentino, R.J. and Berridge, C.W. (2004) Organization of Hypocretin/Orexin Efferents to Locus Coeruleus and Basal Forebrain Arousal‐Related Structures. Journal of Comparative Neurology , 481, 160-178. https://doi.org/10.1002/cne.20369
Nixon, J.P. and Smale, L. (2007) A Comparative Analysis of the Distribution of Immunoreactive Orexin a and B in the Brains of Nocturnal and Diurnal Rodents. Behav ioral and Brain Functions , 3, Article No. 28. https://doi.org/10.1186/1744-9081-3-28
Peyron, C., Tighe, D.K., van den Pol, A.N., de Lecea, L., Heller, H.C., Sutcliffe, J.G., et al . (1998) Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems. The Journal of Neuroscience , 18, 9996-10015. https://doi.org/10.1523/jneurosci.18-23-09996.1998
Nixon, J.P., Mavanji, V., Butterick, T.A., Billington, C.J., Kotz, C.M. and Teske, J.A. (2015) Sleep Disorders, Obesity, and Aging: The Role of Orexin. Ageing Research Reviews , 20, 63-73. https://doi.org/10.1016/j.arr.2014.11.001
Toor, B., Ray, L.B., Pozzobon, A. and Fogel, S.M. (2021) Sleep, Orexin and Cognition. In: Frontiers of Neurology and Neuroscience , S. Karger AG, 38-51. https://doi.org/10.1159/000514960
Alexandre, C., Andermann, M.L. and Scammell, T.E. (2013) Control of Arousal by the Orexin Neurons. Current Opinion in Neurobiology , 23, 752-759. https://doi.org/10.1016/j.conb.2013.04.008
Hunt, N.J., Rodriguez, M.L., Waters, K.A. and Machaalani, R. (2015) Changes in Orexin (Hypocretin) Neuronal Expression with Normal Aging in the Human Hypothalamus. Neurobiology of Aging , 36, 292-300. https://doi.org/10.1016/j.neurobiolaging.2014.08.010
Shimizu, S., Takenoshita, N., Inagawa, Y., Tsugawa, A., Hirose, D., Kaneko, Y., et al . (2019) Positive Association between Cognitive Function and Cerebrospinal Fluid Orexin a Levels in Alzheimer’s Disease. Journal of Alzheimer ’ s Disease , 73, 117-123. https://doi.org/10.3233/jad-190958
Salomon, R.M., Ripley, B., Kennedy, J.S., Johnson, B., Schmidt, D., Zeitzer, J.M., et al . (2003) Diurnal Variation of Cerebrospinal Fluid Hypocretin-1 (Orexin-A) Levels in Control and Depressed Subjects. Biological Psychiatry , 54, 96-104. https://doi.org/10.1016/s0006-3223(02)01740-7
Evans, A.M., Fornasini, G., Meola, T.R., Gahl, W.A., Huizing, M., Polasek, T.M., et al . (2024) Impact of Food on the Oral Absorption of N‐Acetyl‐d‐Mannosamine in Healthy Men and Women. Clinical Pharmacology in Drug Development , 13, 876-883. https://doi.org/10.1002/cpdd.1433
Schwarzkopf, M., Knobeloch, K., Rohde, E., Hinderlich, S., Wiechens, N., Lucka, L., et al . (2002) Sialylation Is Essential for Early Development in Mice. Proceeding s of the National Academy of Sciences , 99, 5267-5270. https://doi.org/10.1073/pnas.072066199
Hayakawa, K., Sakamoto, Y., Kanie, O., Ohtake, A., Daikoku, S., Ito, Y., et al . (2017) Reactivation of Hyperglycemia-Induced Hypocretin (HCRT) Gene Silencing by N -Acetyl-D-Mannosamine in the Orexin Neurons Derived from Human Ips Cells. Epi genetics , 12, 764-778. https://doi.org/10.1080/15592294.2017.1346775
Kuwahara, M., Ito, K., Hayakawa, K., Yagi, S. and Shiota, K. (2015) N-Acetylmannosamine Improves Sleep-Wake Quality in Middle-Aged Mice: Relevance to Autonomic Nervous Function. Autonomic Neuroscience , 187, 56-62. https://doi.org/10.1016/j.autneu.2014.11.005
Yamaguchi, S., Ohnishi, J., Maru, I. and Ohta, Y. (2006) Simple and Large-Scale Production of N-Acetylneuraminic Acid and N-Acetyl-D-Mannosamine. Trends in Glycoscience and Glycotechnology , 18, 245-252. https://doi.org/10.4052/tigg.18.245
Kikusui, T., Shimozawa, A., Kitagawa, A., Nagasawa, M., Mogi, K., Yagi, S., et al . (2012) N -Acetylmannosamine Improves Object Recognition and Hippocampal Cell Proliferation in Middle-Aged Mice. Bioscience , Biotechnology , and Biochemistry , 76, 2249-2254. https://doi.org/10.1271/bbb.120536
Nagasawa, M., Shimozawa, A., Mogi, K. and Kikusui, T. (2014) N-Acetyl-D-Mannosamine Treatment Alleviates Age-Related Decline in Place-Learning Ability in Dogs. Journal of Veterinary Medical Science , 76, 757-761. https://doi.org/10.1292/jvms.13-0351
Watanabe, H., Okawara, M., Matahira, Y., Mano, T., Wada, T., Suzuki, N., et al . (2020) The Impact of Ascidian ( Halocynthia roretzi )-Derived Plasmalogen on Cognitive Function in Healthy Humans: A Randomized, Double-Blind, Placebo-Controlled Trial. Journal of Oleo Science , 69, 1597-1607. https://doi.org/10.5650/jos.ess20167
Gualtieri, C. and Johnson, L. (2006) Reliability and Validity of a Computerized Neurocognitive Test Battery, CNS Vital Signs. Archives of Clinical Neuropsychology , 21, 623-643. https://doi.org/10.1016/j.acn.2006.05.007
Heuchert, J.P. and McNair, D.M. (2012) Profile of Mood States. 2nd Edition TM, PsycTESTS Dataset.
Amieva, H., Meillon, C., Proust-Lima, C. and Dartigues, J.F. (2019) Is Low Psychomotor Speed a Marker of Brain Vulnerability in Late Life? Digit Symbol Substitution Test in the Prediction of Alzheimer, Parkinson, Stroke, Disability, and Depression. De mentia and Geriatric Cognitive Disorders , 47, 297-305. https://doi.org/10.1159/000500597
Haworth, J., Phillips, M., Newson, M., Rogers, P.J., Torrens-Burton, A. and Tales, A. (2016) Measuring Information Processing Speed in Mild Cognitive Impairment: Clinical versus Research Dichotomy. Journal of Alzheimer ’ s Disease , 51, 263-275. https://doi.org/10.3233/jad-150791
Righart, R., Duering, M., Gonik, M., Jouvent, E., Reyes, S., Hervé, D., et al . (2013) Impact of Regional Cortical and Subcortical Changes on Processing Speed in Cerebral Small Vessel Disease. NeuroImage : Clinical , 2, 854-861. https://doi.org/10.1016/j.nicl.2013.06.006
Corbo, I., Troisi, G., Marselli, G. and Casagrande, M. (2024) The Role of Cognitive Flexibility on Higher Level Executive Functions in Mild Cognitive Impairment and Healthy Older Adults. BMC Psychology , 12, Article No. 317. https://doi.org/10.1186/s40359-024-01807-5
Amir, S.M., Barker, S.A., Butt, W.R., Crooke, A.C. and Davies, A.G. (1966) Administration of N-Acetyl-D-Mannosamine to Mammals. Nature , 211, 976-977. https://doi.org/10.1038/211976a0
Kim, C., Johnson, N.F., Cilles, S.E. and Gold, B.T. (2011) Common and Distinct Mechanisms of Cognitive Flexibility in Prefrontal Cortex. The Journal of Neuroscience , 31, 4771-4779. https://doi.org/10.1523/jneurosci.5923-10.2011
Funahashi, S. and Andreau, J.M. (2013) Prefrontal Cortex and Neural Mechanisms of Executive Function. Journal of Physiology - Paris , 107, 471-482. https://doi.org/10.1016/j.jphysparis.2013.05.001
Davidson, R.J. (2002) Anxiety and Affective Style: Role of Prefrontal Cortex and Amygdala. Biological Psychiatry , 51, 68-80. https://doi.org/10.1016/s0006-3223(01)01328-2
Ganesh, K.A.B., Panda, P., Makwana, A.H., Gopalakrishna, P.K., Rani, K.P. and Vishnumukkala, T. (2024) Unraveling the Amygdala: A Review of Its Anatomy and Functions. Bioinformation , 20, 1588-1592. https://doi.org/10.6026/9732063002001588