The Potential and Challenges of Creatine Supplementation for Cognition/Memory in Older Adults


  • Marco Machado
  • Rafael Pereira

Received Date: 28.09.2022 Accepted Date: 14.11.2022 Eur J Geriatric Gerontol 2023;5(1):1-5

Creatine (Cr) has been proposed as an ergogenic resource and the adhesion to its therapeutic use has gained relevance in the last 2 decades. The role of Cr in the aging process has been highlighted, with many studies aiming to understand how aging affects the depletion of Cr resources in muscle and brain, especially because Cr is a natural regulator of energy homeostasis and plays a recognized role in brain function and development, justifying the rising hypothesis that Cr supplementation can help mitigate the effects of aging. Thus, we aimed to review the role of Cr (supplemented or obtained in daily diet) and its metabolism in the aging brain, with emphasis on cognition/memory. PubMed, PsychInfo, EBSCO, Medline, BioMed central and Science Direct, constituted the searched databases. Inclusion criteria specified peer-reviewed studies investigating creatine metabolism and/or creatine supplementation, and assessing cognition, and memory in old adults, and published between January, 2000 to September, 2022. The importance of creatine in the brain’s energy metabolism is well established. The relationship between the decline of cognitive function and brain creatine storage still lacks stronger evidence. Evidence is also lacking on whether creatine supplementation is beneficial in mitigating the neural effects of aging, remaining an open field of studies that brings optimistic perspectives.

Keywords: Creatine, cognition, brain, memory, aging


Creatine is a nitrogenous compound directly linked to energy metabolism in various organs and tissues. It is proposed as an ergogenic resource for a long time; however, its therapeutic use has gained relevance and adhesion in the last two decades. Interestingly, the role of this metabolite in the aging process has been highlighted, with many studies aiming to understand how aging affects creatine resource depletion (1-4), and how creatine supplementation could mitigate this event (2,5,6). Recent studies have risen the hypothesis that creatine supplementation can help mitigate the effects of aging, supported by the fact that creatine is a natural regulator of energy homeostasis, and plays a recognized role in brain function and development (7). Thus, this mini-review shows the state of the art in the role of creatine (supplemented or obtained in daily diet) and its metabolism in the aging brain, with emphasis on cognition/memory.


The following databases were searched: PubMed, PsychInfo, EBSCO, Medline, BioMed central, and Science Direct. Inclusion criteria specified peer-reviewed studies investigating creatine metabolism and/or creatine supplementation, and assessing cognition, and memory in old adults, and published between January, 2000 to September, 2022. Each author searched for articles separately based on the descriptors “creatine supplementation”, “old people”, “elderly”, and “aging”. After removing duplicate articles and abstracts that did not meet the inclusion criteria, only common articles selected by the authors were adopted.


Creatine Metabolism and Energy Supply

Creatine (methyl guanidine-acetic acid) is derived and synthesized from reactions involving the amino acids arginine, glycine, and methionine in the kidneys and liver or can be ingested exogenously primarily from animal-based foods (i.e., red meat, seafood) or through dietary supplements (8-11). Ninety-five percent of creatine is found in skeletal muscle with the remaining 5% dispersed across the brain, liver, kidney, and testes (8,12). Once creatine is transported into the skeletal muscle, ~2/3 is converted to phosphocreatine (CrP) with the remainder stored as free creatine. Phosphocreatine can be rapidly catabolized via creatine kinase (CK) and acts as a metabolic intermediary of energy transfer by facilitating the rapid re-synthesis of adenosine triphosphate (ATP). The average amount of total creatine stored in the body is ~120 g (for a 70 kg human) and the rate of creatine degradation to creatinine is ~1.7% of the total body creatine pool per day (13,14). To compensate for this daily turnover, the average person requires ~2 g creatine per day, with about half of this daily requirement (1 g) synthesized endogenously and the remainder coming from dietary sources (10,12,15).

Creatine and Brain Metabolism

The brain is a metabolically active tissue, requiring ~20% of total energy consumption, despite only accounting for 2% of total body mass. Creatine content and metabolism impairments have been reported as associated with neurological and psychiatric disorders (7,16,17), rising the hypothesis that creatine intake, in the daily diet or as a supplement, could be of therapeutic value for treating neurologic/psychiatric illnesses (6,18,19).

Creatine is a natural regulator of energy homeostasis, playing a relevant role in brain bioenergetics (7), justifying the neurological disease’s development and profound cognitive impairment due to the inability to synthesize or transport creatine (i.e., creatine deficiency syndrome) (6,18-20). Indeed, CK is expressed in a brain-specific isoform (BB-CK), suggesting that creatine plays a role in energy provision and homeostasis in the central nervous system (CNS) (12,20-22).

Complex cognitive tasks, hypoxia, sleep deprivation, and some neurological conditions are characterized by rapid brain metabolic activity and ATP depletion, where creatine metabolism could be essential for energy homeostasis (21-24). It is important to highlight that the brain creatine content may also decrease with age, and age-related decreases in brain creatine content could be associated with reduced brain activity or disease (22,25).

In addition, deletion of cytosolic brain-type CK in mice was shown to result in slower learning of a spatial task and diminished open-field habituation as well as increased intra- and infra-pyramidal hippocampal mossy fiber area, suggesting that the creatine-CK network is also involved in brain plasticity in addition to metabolism (26).

A growing body of literature shows that creatine supplementation can enhance brain creatine content (20,22). However, it is unclear if habitual dietary intake of creatine from food sources can be sufficient to maintain the brain’s creatine stores as well and cognitive function.

Creatine and Brain Aging

The muscle creatine stores decrease with age, although it is not clear whether this reduction is due to aging or simply associated with declines in the amount of physical activity that elderly individuals engage (20). It is similarly thought that brain creatine levels may also decrease with age, and this may be due to general aging, or it may coincide with reductions in brain activity (22). Regardless of the mechanism, reductions in creatine content and its metabolites may be part of the cognitive capacity impairments, which are typically associated with aging (6). This is supported by data showing that older people with higher resting creatine concentrations tend to perform better in cognitively demanding tasks (6,21).

Aging, Obesity, and Cognition

Outside of aging, obesity may also play a role in cognition since obesity causes structural and functional cerebral microcirculation impairments, which play a crucial role in the pathogenesis of both cognitive impairment and major diseases such as Alzheimer’s disease (27-29). Specifically pathophysiological consequences of cerebromicrovascular dysregulation in obesity have been associated with blood-brain barrier (BBB) disruption, neuroinflammation, exacerbation of neurodegeneration, microvascular rarefaction, and ischemic neuronal dysfunction and damage (27). These alterations are likely to have meaningful consequences on cognition. For example, overweight older women exhibit larger declines in perceptual speed over time than would be expected from normal aging (27). In fact, comparing overweight women to normal body weights ones, the observed decline in perceptual speed suggested an additional 2.4 years of aging (30). The hypothesized mechanism linking obesity and such brain alterations is related to the metabolic activity of adipose tissue, which secretes a variety of adipokines, which signal at both peripheral and central sites (27). Excessive adiposity can result in dysregulated adipokines secretion, many of them with pro-inflammatory effects, rendering the adipose tissue a major contributor to systemic inflammation (29). This low-grade inflammation, induced by circulating pro-inflammatory mediators secreted from adipocytes, is recognized as an important factor in impaired neuronal function and the pathogenesis of cognitive impairment (27).

Reduced selective attention and inhibitory function in overweight older adults affect autonomy, increasing the risk of other age-associated problems (28,29,31). Decreased ability to isolate central and flanked information can lead to postural instability and falls, while correctly discerning the surrounding environment increases autonomy. Previous studies (3,4,32-34) allow us to suggest that creatine intake in daily diet and supplementation can be an ally in maintaining the autonomy and health of old adults (33), not only due to the effects against sarcopenia but also in the maintenance of CNS activity (6,12,21).


One specific cognitive domain that appears critical in aging adults is memory. Memory is the ability to acquire, store and retrieve available information in the brain. It is also the stored information and facts, which were obtained through heard or lived experiences. The typical age-associated CNS function decline impairs the ability to store information and learn new tasks, impacting the quality of life in older adults (26,29-31,35).

Increased brain creatine content, specially CrP, has been shown to preserve the integrity and stability of the cell membrane, such as structural stability and functional maintenance, preventing cell apoptosis caused by abnormal energy metabolism (36). In vitro, creatine has been shown to increase oxidative phosphorylation in synaptosomes and isolated brain mitochondria (37). In rats, creatine injected into the hippocampus enhanced spatial memory and object exploration (38). In addition, cAMP-response element-binding protein (CREB) known to influence memory is upregulated 30 minutes after creatine injection (38). Recently, 4 weeks of creatine supplementation in mice enhanced isolated hippocampal mitochondria and improved memory (39). Further, creatine is important for neuronal protection (40). Future research is warranted to investigate whether creatine intake from a daily diet can alter these potential mechanisms in humans.

Neurodegenerative Diseases

Furthermore, creatine may play a role in the prevention of other neurodegenerative diseases such as Alzheimer’s disease. Alzheimer’s disease is associated with a reduction in brain creatine content and in a recent study using a 3xTg mouse model of Alzheimer’s disease, creatine supplementation over 8-9 weeks exhibited beneficial preventative effects in females (41). It is described that the spatial memory impairments induced by beta-amyloid protein accumulation are greater in females (39,41), while Snow et al. (39,41) showed that the mitigating deleterious effects promoted by creatine supplementation are superior in females. It is important to note that the proposed underlying mechanism is not the decrease in plaque accumulation, but the greater availability of ATP/CrP, reducing the effects of neuronal apoptosis and necrosis, mainly in the hippocampus (39-41). Other proposed mechanistic effect is the down-regulation of the NF-κB inhibitor, IκB, induced by creatine (39). Notwithstanding, neuronal NF-κB regulates the expression of several genes involved in cognition and memory (39).

Creatine as a Needful Nutrient

Ostojic et al. (3) found a significant positive correlation between WAIS III Digit Symbol Substitution Test (DSS) scores and habitual dietary intake of creatine in a larger sample of older adults. Working memory for spatial locations activates the superior prefrontal cortex and posterior parietal cortex, and previous studies (6,42) showed a presence of BB-CK isoform and Cr/PCr in these brain areas, however, brain permeability to circulating creatine is limited due to the absence of creatine transporter expression in the astrocytes involved in crossing the BBB. Since the brain endogenously synthesizes creatine, it is unclear as to the importance of exogenous delivery of creatine, may differ in older adults (6,20). Thus, more specific studies on the association between daily dietary intake, biosynthesis, and creatine concentration in the CNS are needed.

Notwithstanding, the literature is conflicting on the effects of creatine supplementation on cognitive task performance in older adults (20). It is important to highlight that the difficulty in assessing brain creatine concentration is one of the main limitations of this kind of study. Despite the physiological plausibility of the proposed mechanisms for the success of creatine supplementation, added to the positive results. Some studies still show insufficient or contradictory results (15,43,44). The main challenge for the future is to measure the appropriate doses so that the results can be confirmed, increasing the strength of the evidence. 

Approximately 1 g of creatine is converted to creatinine per day, suggesting that 1 g of creatine be ingested or synthesized to replenish reserves (8,10,32,33,45). It is quite common for older adults to have low protein intake, especially from meat (33), possibly due to difficulty in chewing. Older adults may need creatine supplementation beyond increasing dietary intake to help replenish reserves, regardless of whether they increase intracellular stores to improve some skill or competence.


The importance of creatine in the energy metabolism of the brain is already well established. The relationship between the decline of cognitive functions and creatine still lacks stronger evidence. Evidence is also lacking on whether creatine supplementation is beneficial in mitigating the neural effects of aging. Further studies should explore the scientific gaps in this field, as well as investigate the association between creatine supplementation and other interventions, such as exercise training, to minimize/ameliorate brain aging. In summary, it remains an open field of studies that brings plausible perspectives.


Peer-review: Externally peer-reviewed.

Authorship Contributions

Concept: M.M., R.P., Design: M.M., R.P., Analysis or Interpretation: M.M., R.P., Literature Search: M.M., R.P., Writing: M.M., R.P.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

  1. Forbes SC, Candow DG, Ostojic SM, Roberts MD, Chilibeck PD. Meta-analysis examining the importance of creatine ingestion strategies on lean tissue mass and strength in older adults. Nutrients 2021;13:1912.
  2. Rawson ES, Venezia AC. Use of creatine in the elderly and evidence for effects on cognitive function in young and old. Amino Acids 2011;40:1349-1362.
  3. Ostojic SM, Korovljev D, Stajer V. Dietary creatine and cognitive function in U.S. adults aged 60 years and over. Aging Clin Exp Res 2021;33:3269-3274.
  4. Machado M, Masterson TD, Oliveira EF. Could dietary creatine intake modulate overweight elderly’s selective attention and inhibitory function? Nutr Health 2022;026010602211274.
  5. Dos Santos EEP, de Araújo RC, Candow DG, Forbes SC, Guijo JA, de Almeida Santana CC, Prado WLD, Botero JP. Efficacy of creatine supplementation combined with resistance training on muscle strength and muscle mass in older females: A systematic review and meta-analysis. Nutrients 2021;13:3757.
  6. Avgerinos KI, Spyrou N, Bougioukas KI, Kapogiannis D. Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials. Exp Gerontol 2018;108:166-173.
  7. Allen PJ. Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value? Neurosci Biobehav Rev 2012;36:1442-1462.
  8. Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev 2000;80:1107-1213.
  9. Ellery SJ, Walker DW, Dickinson H. Creatine for women: a review of the relationship between creatine and the reproductive cycle and female-specific benefits of creatine therapy. Amino Acids 2016;48:1807-1817.
  10. Alraddadi EA, Lillico R, Vennerstrom JL, Lakowski TM, Miller DW. Absolute Oral Bioavailability of Creatine Monohydrate in Rats: Debunking a Myth. Pharmaceutics 2018;10:31.
  11. Antonio J, Candow DG, Forbes SC, Gualano B, Jagim AR, Kreider RB, Rawson ES, Smith-Ryan AE, VanDusseldorp TA, Willoughby DS, Ziegenfuss TN. Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show? J Int Soc Sports Nutr 2021;18:13.
  12. Rackayova V, Cudalbu C, Pouwels PJW, Braissant O. Creatine in the central nervous system: From magnetic resonance spectroscopy to creatine deficiencies. Anal Biochem 2017;529:144-457.
  13. Brosnan JT, da Silva RP, Brosnan ME. The metabolic burden of creatine synthesis. Amino Acids 2011;40:1325-1331.
  14. Persky AM, Brazeau GA, Hochhaus G. Pharmacokinetics of the dietary supplement creatine. Clin Pharmacokinet 2003;42:557-574.
  15. Candow DG, Forbes SC, Kirk B, Duque G. Current Evidence and Possible Future Applications of Creatine Supplementation for Older Adults. Nutrients 2021;13:745.
  16. Klein AM, Ferrante RJ. The neuroprotective role of creatine. Subcell Biochem 2007;46:205-243.
  17. Andres RH, Ducray AD, Schlattner U, Wallimann T, Widmer HR. Functions and effects of creatine in the central nervous system. Brain Res Bull 2008;76:329-343.
  18. Wyss M, Schulze A. Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease? Neuroscience 2002;112:243-260.
  19. Tarnopolsky MA, Beal MF. Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Ann Neurol 2001;49:561-574.
  20. Roschel H, Gualano B, Ostojic SM, Rawson ES. Creatine supplementation and brain health. Nutrients 2021;13:586.
  21. Riesberg LA, Weed SA, McDonald TL, Eckerson JM, Drescher KM. Beyond muscles: The untapped potential of creatine. Int Immunopharmacol 2016;37:31-42.
  22. Dolan E, Gualano B, Rawson ES. Beyond muscle: the effects of creatine supplementation on brain creatine, cognitive processing, and traumatic brain injury. Eur J Sport Sci 2019;19:1-14.
  23. Gerbatin RR, Silva LFA, Hoffmann MS, Della-Pace ID, do Nascimento PS, Kegler A, de Zorzi VN, Cunha JM, Botelho P, Neto JBT, Furian AF, Oliveira MS, Fighera MR, Royes LFF. Delayed creatine supplementation counteracts reduction of GABAergic function and protects against seizures susceptibility after traumatic brain injury in rats. Prog Neuropsychopharmacol Biol Psychiatry 2019;92:328-338.
  24. Rae CD, Bröer S. Creatine as a booster for human brain function. How might it work? Neurochem Int 2015;89:249-259.
  25. Ostojic SM, Forbes SC. Perspective: Creatine, a Conditionally Essential Nutrient: Building the Case. Adv Nutr 2022;13:34-37.
  26. Rae C, Digney AL, McEwan SR, Bates TC. Oral creatine monohydrate supplementation improves brain performance: A double-blind, placebo-controlled, cross-over trial. Proc Biol Sci 2003;270:2147-2150.
  27. Balasubramanian P, Kiss T, Tarantini S, Nyúl-Toth Á, Ahire C, Yabluchanskiy A, Csipo T, Lipecz A, Tabak A, Institoris A, Csiszar A, Ungvari Z. Obesity-induced cognitive impairment in older adults: A microvascular perspective. Am J Physiol Heart Circ Physiol 2021;320:H740-H761.
  28. Salthouse TA. When does age-related cognitive decline begin? Neurobiol Aging 2009;30:507-514.
  29. Batsis JA, Haudenschild C, Roth RM, Gooding TL, Roderka MN, Masterson T, Brand J, Lohman MC, Mackenzie TA. Incident Impaired Cognitive Function in Sarcopenic Obesity: Data From the National Health and Aging Trends Survey. J Am Med Dir Assoc 2021;22:865-872.e5.
  30. Kazlauskaite R, Janssen I, Wilson RS, Appelhans BM, Evans DA, Arvanitakis Z, El Khoudary SR, Kravitz HM. Is Midlife Metabolic Syndrome Associated With Cognitive Function Change? The Study of Women’s Health Across the Nation. J Clin Endocrinol Metab 2020;105:e1093-e1105.
  31. Dehn MJ. Working Memory and Academic Learning. New Jersey: John Wiley & Sons; 2011.
  32. Ostojic SM. Dietary creatine intake in U.S. population: NHANES 2017-2018. Nutrition 2021;87-88:111207.
  33. Ostojic SM. Creatine as a food supplement for the general population. J Funct Foods 2021;83:104568.
  34. Oliveira EF, Forbes SC, Borges EQ, Machado LF, Candow DG, Machado M. Association between dietary creatine and visuospatial short-term memory in older adults. Nutr Health 2022;22:2601060221102273.
  35. Foret JT, Oleson S, Hickson B, Valek S, Tanaka H, Haley AP. Metabolic Syndrome and Cognitive Function in Midlife. Arch Clin Neuropsychol 2021;36:897-907.
  36. Tokarska-Schlattner M, Epand RF, Meiler F, Zandomeneghi G, Neumann D, Widmer HR, Meier BH, Epand RM, Saks V, Wallimann T, Schlattner U. Phosphocreatine interacts with phospholipids, affects membrane properties and exerts membrane-protective effects. PLoS One 2012;7:e43178.
  37. Monge C, Beraud N, Kuznetsov A V, Rostovtseva T, Sackett D, Schlattner U, Vendelin M, Saks VA. Regulation of respiration in brain mitochondria and synaptosomes: restrictions of ADP diffusion in situ, roles of tubulin, and mitochondrial creatine kinase. Mol Cell Biochem 2008;318:147-165.
  38. Souza MA, Magni DV, Guerra GP, Oliveira MS, Furian AF, Pereira L, Marquez SV, Ferreira J, Fighera MR, Royes L. Involvement of hippocampal CAMKII/CREB signaling in the spatial memory retention induced by creatine. Amino Acids 2012;43:2491-2503.
  39. Snow WM, Cadonic C, Cortes-Perez C, Roy Chowdhury SK, Djordjevic J, Thomson E, Bernstein MJ, Suh M, Fernyhough P, Albensi BC. Chronic dietary creatine enhances hippocampal-dependent spatial memory, bioenergetics, and levels of plasticity-related proteins associate. Learn Mem 2018;25:54-66.
  40. Liu W, Qaed E, Zhu HG, Dong MX, Tang ZY. Non-energy mechanism of phosphocreatine on the protection of cell survival. Biomed Pharmacother. 2021;141:111839.
  41. Snow WM, Cadonic C, Cortes-Perez C, Adlimoghaddam A, Roy Chowdhury SK, Thomson E, Anozie A, Bernstein MJ, Gough K, Fernyhough P, Suh M, Albensi BC. Sex-Specific Effects of Chronic Creatine Supplementation on Hippocampal-Mediated Spatial Cognition in the 3xTg Mouse Model of Alzheimer’s Disease. Nutrients 2020;12:3589.
  42. Merege-Filho CAA, Otaduy MCG, De Sá-Pinto AL, De Oliveira MO, De Souza Gonçalves L, Hayashi AP, Roschel H, Pereira RM, Silva CA, Brucki SM, da Costa Leite C, Gualano B. Does brain creatine content rely on exogenous creatine in healthy youth? A proof-of-principle study. Appl Physiol Nutr Metab 2017;42:128-134.
  43. Forbes SC, Candow DG, Ferreira LHB, Souza-Junior TP. Effects of Creatine Supplementation on Properties of Muscle, Bone, and Brain Function in Older Adults: A Narrative Review. J Diet Suppl 2022;19:318-335.
  44. Candow DG, Chilibeck PD, Forbes SC, Fairman CM, Gualano B, Roschel H. Creatine supplementation for older adults: Focus on sarcopenia, osteoporosis, frailty and Cachexia. Bone 2022;162:116467.
  45. Deldicque L, Décombaz J, Zbinden Foncea H, Vuichoud J, Poortmans JR, Francaux M. Kinetics of creatine ingested as a food ingredient. Eur J Appl Physiol 2008;102:133-143.