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Cited by 43Muscle metabolism and nutritionNutrition and Health in AgingBiochemical effects in animals

The DOI matches its Crossref record; 286 of the 287 references it cites were found in a registry or an index, and 1 are not checked yet; none of the 259 sources its claims cite is checked for support yet.

Creatine monohydrate supplementation for older adults and clinical populations

Open access
Candow, Darren G., Ostojic, Sergej M., Chilibeck, Philip D., Longobardi, Igor, Gualano, Bruno, Tarnopolsky, Mark A., Wallimann, Theo, Moriarty, Terence, Kreider, Richard B., Forbes, Scott C., Schlattner, Uwe, Antonio, Jose·2025·Journal of the International Society of Sports Nutrition
DOI 10.1080/15502783.2025.2534130PMC PMC12272710
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Abstract

BACKGROUND: The biological process of aging is typically associated with a decrease in muscle quantity, muscle performance (primarily strength), bone mass and architecture, functionality and neurological/cognitive function. From a healthy aging perspective, interventions that have the potential to overcome or attenuate these decrements are clinically relevant. METHODS: We conducted a narrative review on the efficacy of creatine monohydrate supplementation (CrM) in older adults. RESULTS: Accumulating research shows that CrM, primarily when combined with exercise training, is safe and has beneficial effects on measures of whole-body lean body mass, regional muscle size, muscle strength, bone area and thickness, functional ability, glucose kinetics, cognition and memory. CONCLUSION: CrM has multiple benefits in older adults and may have application for treating age-related sarcopenia, osteoporosis, frailty, and those with metabolic and neuromuscular disorders.

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Overview

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TL;DR

This narrative review concludes that creatine monohydrate (CrM), especially with exercise training, is safe and has multiple benefits in older adults, including lean mass, strength, bone, function, glucose metabolism, and cognition. It also discusses potential applications for age-related sarcopenia, osteoporosis, frailty, metabolic disorders, neuromuscular disorders, and brain aging.

Key findings

  • CrM combined with resistance training improves upper-body strength (SMD 0.24, p = 0.02) and hand-grip strength (SMD 0.23, p = 0.04) in older adults; lower-body strength effects are less robust (SMD 0.17, p = 0.09; SMD 0.07, p = 0.61), though a loading phase followed by >5 g/day improved lower-body strength (SMD 0.29, p = 0.02) while no loading phase did not (SMD 0.06, p = 0.69). CrM (≥3 g/day) plus resistance training increases whole-body lean mass by ~1.2 kg more than resistance training alone in healthy, non-frail older adults.
  • Bone and fall-related outcomes: 10 weeks of CrM (0.1 g/kg on training days) decreased urinary cross-linked N-telopeptides of type I collagen by 27% versus a 13% increase with placebo. One-year CrM plus resistance training attenuated femoral neck bone mineral density loss in postmenopausal women (1.2% loss vs 3.9% with placebo), but this was not replicated in a larger two-year study; two years of CrM improved some bone geometric properties, though changes were small and may be below clinical thresholds. Only one study assessed actual falls and found no effect (n = 237, likely underpowered).
  • Metabolic and clinical populations: in type 2 diabetes, CrM (5 g/day for 12 weeks) plus exercise led to greater reductions in glycemia and HbA1c and improved glucose tolerance and GLUT-4 translocation. In Alzheimer’s disease, CrM (20 g/day for 8 weeks) increased brain total creatine by 11% and improved cognition/memory in 20 older adults. A safety analysis of 32 published studies and 1,232 older participants found no significant differences in any evaluated side effects.
  • Neuromuscular disorders: evidence is mixed by condition; the 2013 Cochrane review supports CrM (~0.1 g/kg/day) improving strength (~8.5%) and lean mass (~0.63 kg) in muscular dystrophy, but data do not support CrM in ALS or CPEO, and there is too little data in peripheral nerve or neuromuscular junction disorders.

Methods

  • Design: narrative review on the efficacy and safety of CrM in older adults and clinical populations.
  • Data: synthesized published literature, including meta-analyses, randomized controlled trials, small clinical studies, and preclinical/mechanistic work; no new primary data were collected.
  • Analysis: narrative synthesis of effects on muscle, bone, falls/frailty, metabolic disorders, neuromuscular disorders, brain/cognition, safety, and food-sourced creatine.

Limitations

  • Stated by the paper: safety research in older adults is limited, often derived from secondary outcomes of efficacy studies with variable doses/durations and limited safety indicators; drug-nutrient interactions and effects of age-related pharmacokinetic/pharmacodynamic changes are understudied. Research in older clinical populations is scarce, mostly small-scale, short-term, and exploratory; dietary creatine intake estimates rely on recall with high variability; bone changes may be comparable to precision errors or below clinical significance; fracture and fall studies were underpowered.
  • Stated by the paper: cognitive findings are inconsistent, possibly because standard CrM protocols produce limited increases in brain creatine in older adults, and there is substantial inter-individual variation in brain creatine; chronological age alone should not determine supplementation need.
  • Evident from the text: as a narrative review, it does not report a systematic search strategy or formal risk-of-bias assessment; many mechanistic claims are based on young populations or animal/preclinical models and have not been substantiated in older adults, and lower-body strength findings remain mixed.

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Registry

Crossref · 10.1080/15502783.2025.2534130

Cites

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Statistics

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Figures

Figure 1. The energy buffer function of the CK-system: PCr as temporal energy reservoir A) model calculations for changes in pool sizes of energy-related metabolites during cell stimulation until exhaustion. Global cellular concentration changes in phospho-creatine [PCr] and adenine nucleotides ([ATP], [ADP] and [AMP]), inorganic phosphate [Pi], and creatine [Cr] are calculated from the reactions of creatine kinase (CK), adenylate kinase and a generalized ATPase. The decreasing “high-energy” phosphates (total ˜P), represented by PCr and ATP, correspond to a transition from rest to high workload and finally exhaustion. At rest, [PCr] and [ATP] are high, while [ADP] is very low and [AMP] is virtually non-measurable. Note that with high-energy phosphate consumption, [ATP] remains constant until more than 80% of the PCr pool is consumed, and only then do [ADP] and later [AMP] start to rise. [Cr] rises proportionally with the decrease of [PCr], and [Pi] increases linearly with the decrease of [PCr] and [adenine nucleotides] combined. Note that during cellular work with increasing PCr depletion, the concentration of Cr, Pi and ADP are increasing and all three are stimulating oxidative phosphorylation for production of ATP by mitochondria, while rising Pi additionally stimulates glycogenolysis and glycolysis to even generate more ATP. Thus, the CK-system serves as an energy buffer to keep [ATP] and the ATP/ADP ratio high and thus guarantees for a high subcellular phosphorylation potential ([Atp]/[ADP]*[pi]), near the various ATPases, where CK is specifically colocalized with- and functionally coupled to- the latter (modified from ref [46]).
Figure 1. The energy buffer function of the CK-system: PCr as temporal energy reservoir A) model calculations for changes in pool sizes of energy-related metabolites during cell stimulation until exhaustion. Global cellular concentration changes in phospho-creatine [PCr] and adenine nucleotides ([ATP], [ADP] and [AMP]), inorganic phosphate [Pi], and creatine [Cr] are calculated from the reactions of creatine kinase (CK), adenylate kinase and a generalized ATPase. The decreasing “high-energy” phosphates (total ˜P), represented by PCr and ATP, correspond to a transition from rest to high workload and finally exhaustion. At rest, [PCr] and [ATP] are high, while [ADP] is very low and [AMP] is virtually non-measurable. Note that with high-energy phosphate consumption, [ATP] remains constant until more than 80% of the PCr pool is consumed, and only then do [ADP] and later [AMP] start to rise. [Cr] rises proportionally with the decrease of [PCr], and [Pi] increases linearly with the decrease of [PCr] and [adenine nucleotides] combined. Note that during cellular work with increasing PCr depletion, the concentration of Cr, Pi and ADP are increasing and all three are stimulating oxidative phosphorylation for production of ATP by mitochondria, while rising Pi additionally stimulates glycogenolysis and glycolysis to even generate more ATP. Thus, the CK-system serves as an energy buffer to keep [ATP] and the ATP/ADP ratio high and thus guarantees for a high subcellular phosphorylation potential ([Atp]/[ADP]*[pi]), near the various ATPases, where CK is specifically colocalized with- and functionally coupled to- the latter (modified from ref [46]).CC BY · PubMed Central
Figure 2. The CK–phosphocreatine shuttle: PCr/Cr for intra-cellular energy transport creatine (Cr), either synthesized in the body or taken up from alimentary sources, e.g. meat and fish, is transported by a specific creatine transporter (CRT) into muscle and other cells that require high and fluctuating energy use. Imported Cr is charged to the high-energy compound phosphocreatine (PCr) by the action either of soluble cytosolic CK (CKc), by CK coupled to glycolysis (CKg), or by mitochondrial CK (MtCK). According to the CK equilibrium reaction, in a resting cell, this results in approximately 2/3 of PCr and 1/3 of Cr and in a very high ATP/ADP ratio of more than 100:1. Some fraction of cytosolic CK is specifically associated (CKa) with ATP-consuming processes (ATPases), such as the myofibrillar actomyosin ATPase, the SR Ca2+-ATPase, the plasma membrane Na+/K+-ATPase, the ATP-gated K+-channel, or with ATP-dependent cell signaling. There, CK regenerates directly in situ all the ATP utilized by these processes, drawing from the large PCr pool. This represents the ATP-consuming end of the PCr shuttle.
Figure 2. The CK–phosphocreatine shuttle: PCr/Cr for intra-cellular energy transport creatine (Cr), either synthesized in the body or taken up from alimentary sources, e.g. meat and fish, is transported by a specific creatine transporter (CRT) into muscle and other cells that require high and fluctuating energy use. Imported Cr is charged to the high-energy compound phosphocreatine (PCr) by the action either of soluble cytosolic CK (CKc), by CK coupled to glycolysis (CKg), or by mitochondrial CK (MtCK). According to the CK equilibrium reaction, in a resting cell, this results in approximately 2/3 of PCr and 1/3 of Cr and in a very high ATP/ADP ratio of more than 100:1. Some fraction of cytosolic CK is specifically associated (CKa) with ATP-consuming processes (ATPases), such as the myofibrillar actomyosin ATPase, the SR Ca2+-ATPase, the plasma membrane Na+/K+-ATPase, the ATP-gated K+-channel, or with ATP-dependent cell signaling. There, CK regenerates directly in situ all the ATP utilized by these processes, drawing from the large PCr pool. This represents the ATP-consuming end of the PCr shuttle.CC BY · PubMed Central
Figure 3. The mitochondrial side of the PCr/Cr-shuttle: production of high-energy PCr by mitochondria. In this scheme, ATP generated by oxidative phosphorylation via the F1-ATPase (1) is transported through the mitochondrial inner membrane (IM) by the adenosine nucleotide transporter (ANT) (2) in exchange for ADP. This ATP is preferentially accepted and trans-phosphorylated into PCr by octameric MtCK in the intermembrane space (3). Under certain circumstances, some of this ATP may also be directly exported through the voltage-dependent anion carrier (VDAC) (at left) [58]. However, it is preferentially PCr that leaves the mitochondrion via VDAC (at right) to which MtCK can directly interact with in a Ca2+-dependent fashion. This PCr then feeds into the large cytosolic PCr pool (4). ADP generated from the MtCK transphosphorylation reaction is accepted by ANT and immediately transported back into the matrix (5) to be recharged by the F1-ATPase (1). In contact sites, this substrate channeling allows for a constant supply of substrates and concomitant removal of products at the active sites of MtCK. In cristae, where MtCK is also localized, only ATP/ADP exchange is facilitated through direct channeling to the MtCK active site, while Cr and PCr have to diffuse along the cristae space to reach the VDAC (not shown here, for details, see [55]). Interaction of MtCK with cardiolipin in the mitochondrial inner membrane (IM) surrounding ANT, as well as tight functional coupling of MtCK to ANT leads to saturation of the ANT on the outer side of the IM with ADP, which is transported back into the matrix (5) to be recharged by the F1-ATPase (1), thus efficiently coupling electron transport to ATP generation and at the same time lowering the production of free oxygen radicals (ROS) [57]. On the other hand, the tight functional coupling of ANT to MtCK leads to a saturation of MtCK with ANT-delivered ATP and a locally high ATP:ADP ratio in the vicinity of MtCK, and in combination with cytosolic Cr, entering the intermembrane space via VDAC (at the left), it drives the synthesis by MtCK of PCr from ATP without a loss of its energy content, thus maintaining maximal thermodynamic efficiency for high-energy phosphate synthesis in the form of PCr (4), which then is exported into the cytosol. This explains why Cr stimulates mitochondrial respiration via the action of MtCK [56] (adapted from [46,55]).
Figure 3. The mitochondrial side of the PCr/Cr-shuttle: production of high-energy PCr by mitochondria. In this scheme, ATP generated by oxidative phosphorylation via the F1-ATPase (1) is transported through the mitochondrial inner membrane (IM) by the adenosine nucleotide transporter (ANT) (2) in exchange for ADP. This ATP is preferentially accepted and trans-phosphorylated into PCr by octameric MtCK in the intermembrane space (3). Under certain circumstances, some of this ATP may also be directly exported through the voltage-dependent anion carrier (VDAC) (at left) [58]. However, it is preferentially PCr that leaves the mitochondrion via VDAC (at right) to which MtCK can directly interact with in a Ca2+-dependent fashion. This PCr then feeds into the large cytosolic PCr pool (4). ADP generated from the MtCK transphosphorylation reaction is accepted by ANT and immediately transported back into the matrix (5) to be recharged by the F1-ATPase (1). In contact sites, this substrate channeling allows for a constant supply of substrates and concomitant removal of products at the active sites of MtCK. In cristae, where MtCK is also localized, only ATP/ADP exchange is facilitated through direct channeling to the MtCK active site, while Cr and PCr have to diffuse along the cristae space to reach the VDAC (not shown here, for details, see [55]). Interaction of MtCK with cardiolipin in the mitochondrial inner membrane (IM) surrounding ANT, as well as tight functional coupling of MtCK to ANT leads to saturation of the ANT on the outer side of the IM with ADP, which is transported back into the matrix (5) to be recharged by the F1-ATPase (1), thus efficiently coupling electron transport to ATP generation and at the same time lowering the production of free oxygen radicals (ROS) [57]. On the other hand, the tight functional coupling of ANT to MtCK leads to a saturation of MtCK with ANT-delivered ATP and a locally high ATP:ADP ratio in the vicinity of MtCK, and in combination with cytosolic Cr, entering the intermembrane space via VDAC (at the left), it drives the synthesis by MtCK of PCr from ATP without a loss of its energy content, thus maintaining maximal thermodynamic efficiency for high-energy phosphate synthesis in the form of PCr (4), which then is exported into the cytosol. This explains why Cr stimulates mitochondrial respiration via the action of MtCK [56] (adapted from [46,55]).CC BY · PubMed Central

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Citations

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  1. 10.1249/mss.0000000000000220 · DOI · Paper page
  2. 10.1002/(sici)1097-4598(199710)20:10<1242::aid-mus6>3.0.co;2-c · DOI
  3. 10.1002/(sici)1097-4598(199712)20:12<1502::aid-mus4>3.0.co;2-c · DOI · Paper page
  4. 10.2147/oajsm.s123529 · DOI · Paper page
  5. 10.1093/gerona/58.1.b11 · DOI · Paper page

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Metadata

Authors
Candow, D. G., Ostojic, S. M., Chilibeck, P. D., Longobardi, I., Gualano, B., Tarnopolsky, M. A., Wallimann, T., Moriarty, T., Kreider, R. B., Forbes, S. C., Schlattner, U., & Antonio, J.
Affiliations
  • University of Regina (CA)
  • University of Agder, Department of Nutrition and Public Health
  • University of Saskatchewan (CA)
  • Universidade de São Paulo (BR)
  • McMaster Children's Hospital (CA)
  • ETH Zurich (CH)
  • University of Northern Iowa (US)
  • Texas A&M University (US)
  • Brandon University (CA)
  • Inserm (FR)
  • Nova Southeastern University, Department of Health and Human Performance
Corresponding author
Candow, Darren G.
ORCID
Venue
Journal of the International Society of Sports Nutrition
Publisher
Informa UK Limited
Published
2025-07-17
Volume
22
Issue
sup1
Pages
2534130-2534130
ISSN
1550-2783 (ISSN-L)
DOI
10.1080/15502783.2025.2534130
PMC
PMC12272710
OpenAlex
W4412489008
Semantic Scholar
292d914f399854b2e18dfdd8161aa09a01453af4
Cited by
43
References
286
Citations by year
2026: 37 · 2025: 6
FWCI
4.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the International Society of Sports Nutrition (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • Repository for Publications and Research Data (ETH Zurich) (publishedVersion, cc-by)
  • UNI ScholarWorks (University of Northern Iowa) (submittedVersion, cc-by)
  • HAL (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • ETH Zürich Research Collection
Funders
São Paulo Research Foundation (FAPESP), Brasil (#2021/13580–1)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
  • Health Sciences › Medicine › Physiology (medical) › Nutrition and Health in Aging
  • Health Sciences › Medicine › Physiology (medical) › Biochemical effects in animals
Keywords
creatine monohydrate, older adults, aging, sarcopenia, osteoporosis, frailty, muscle strength, lean body mass, bone mass, functional capacity, glucose kinetics, cognition, memory, exercise training, neuromuscular disorders, metabolic disorders
MeSH terms
Frailty, Aged, Aging, Cognition, Creatine, Humans, Osteoporosis, Exercise, Muscle, Skeletal, Dietary Supplements, Muscle Strength, Sarcopenia

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