Advanced glycation end products (AGEs) with multiple structures are formed at the sites where carbonyl groups of reducing sugars bind to free amino groups of proteins through the Maillard reaction. In recent years, it has been highlighted that the accumulation of AGEs, which are generated when carbonyl compounds produced in the process of sugar metabolism react with proteins, is involved in various diseases. Creatine is a biocomponent that is homeostatically present throughout the body and is known to react nonenzymatically with α-dicarbonyl compounds. This study evaluated the antiglycation potential of creatine against methylglyoxal (MGO), a glucose metabolite that induces carbonyl stress with formation of AGEs in vitro. Further, to elucidate the mechanism of the cytoprotective action of creatine, its effect on the accumulation of carbonyl proteins in the cells and the MGO-induced cellular damage were investigated using neuroblastoma cells. The results revealed that creatine significantly inhibits protein carbonylation by directly reacting with MGO, and creatine added to the culture medium suppressed MGO-derived carbonylation of intracellular proteins and exerted a protective effect on MGO-induced cytotoxicity. These findings suggest that endogenous and supplemented creatine may contribute to the attenuation of carbonyl stress in vivo. 

Elucidating the Antiglycation Effect of Creatine on Methylglyoxal-Induced Carbonyl Stress In Vitro

Adult neurogenesis is well established in canonical niches—the dentate gyrus and the subventricular zone, where aerobic exercise reliably enhances progenitor proliferation, survival, and synaptic integration via increased cerebral blood flow, neurotrophins (e.g., BDNF, IGF-1), neurotransmitter regulation, and reduced neuroinflammation. Nutraceuticals (e.g., polyphenols, omega-3, creatine, vitamins) further support neuroplasticity and neuronal survival through convergent trophic, anti-inflammatory, and metabolic pathways. By contrast, the hypothalamus, a metabolically pivotal, non-canonical niche, remains comparatively understudied. Here, we synthesize anatomical and functional features of hypothalamic neural stem cells, primarily tanycytes (α1, α2, β1, β2), which line the third ventricle and differentially contribute to neuronal activity regulation, metabolic signaling, and cerebrospinal fluid–portal vasculature coupling, thereby linking neurogenesis to endocrine control. Notably, tanycytes can form neurospheres in vitro, enabling mechanistic interrogation. Although evidence for adult hypothalamic neurogenesis in humans is debated due to methodological constraints, animal data suggest potential relevance to disorders characterized by neuronal loss, metabolic dysregulation, and impaired neuroendocrine function. We propose that an integrative framework is timely: exercise and diet likely interact in the hypothalamic niche through shared mediators (BDNF, IGF-1, CNTF, GPR40) and exercise-derived signals (e.g., lactate, IL-6) that may be complemented by defined nutraceuticals. Yet critical uncertainties persist, including the extent of bona fide hypothalamic neurogenesis, nucleus-specific responses (arcuate nucleus, paraventricular nucleus, ventromedial hypothalamic nucleus), and the mechanistic integration of lifestyle signals in this region. To address these gaps, we outline actionable priorities: (i) single-cell and lineage-tracing studies of tanycyte subtypes under distinct training modalities (aerobic, high-intensity interval training, resistance); (ii) combinatorial interventions pairing structured exercise with nutraceuticals to test synergy on progenitor dynamics and inflammation; and (iii) multi-omics and translational studies to identify biomarkers and establish clinical relevance. Clarifying these interactions will determine whether lifestyle and supplementation strategies can synergistically modulate hypothalamic neurogenesis and inform therapies for neurological, neuropsychiatric, and metabolic disorders. 

Perspective for Modulation of Hypothalamic Neurogenesis: Integrating Anatomical Insights with Exercise and Dietary Interventions

Creatine, widely known as a performance-enhancing supplement for athletes and bodybuilders is increasingly recognized for its potential neuroprotective properties. Beyond its well-established role in energy metabolism and muscle physiology, creatine appears to influence brain function by supporting ATP homeostasis, reducing oxidative stress, and stabilizing neuronal membranes. Recent studies have suggested that creatine supplementation may benefit individuals with neurodegenerative disorders such as Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease. Additionally, preliminary findings indicate a potential role for creatine in mitigating the effects of acute brain injuries and mood disorders, including major depressive disorder. Despite promising experimental data, the clinical efficacy of creatine in neurological settings remains under investigation, with inconsistent results across human trials. This review aims to summarize current knowledge on the neuroprotective effects of creatine and critically assess the quality of available evidence. 

pdf/the-role-of-creatine-in-neurological-disorders-a-literature-m7i0cyl67i3a.pdf

The role of creatine in neurological disorders: a literature review

Cerebrospinal fluid (CSF) biomarkers can directly reflect physiological and pathological changes within the central nervous system, serving as a critical element in the preliminary diagnosis and disease monitoring of central nervous system disorders. Specific CSF biomarker patterns may be associated with different types of dementia. The goal of this analysis is to scrutinize the causal correlation between 338 CSF biomarkers and the danger of 4 dementia categories, namely Alzheimer disease, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies, using Mendelian randomization (MR) analysis. Forward and reverse MR were employed to examine this causal relationship. Inverse variance weighting was used as the primary statistical method, with weighted median, MR-Egger, simple mode, and weighted mode methods as supplementary approaches. Concurrently, scrutiny of horizontal pleiotropy, heterogeneity, and sensitivity was undertaken to substantiate the inferences made from the MR study. We identified 9 positive and 12 negative causal relationships between genetic predisposition to CSF biomarkers and dementia. Notably, a bidirectional causal relationship was found between 3-methoxytyrosine levels and Alzheimer disease. The findings of this MR study support a causal association between CSF biomarkers and the risk of 4 distinct types of dementia. 

Mapping cerebrospinal fluid biomarkers to dementia risk through Mendelian randomization

Alzheimer’s Disease (AD) is a systemic metabolic disease with a variable number and type of clinical symptoms mostly impacting the brain. Skin carotenoid content (SCC) is an objective measure of carotenoid‐containing fruit and vegetable intake that has been validated in diverse populations. Our previous findings suggest SCC scores are impacted by various metabolic disease states. Therefore, our objective was to analyze SCC scores and dietary intake across matched pairs including unimpaired adults and those with AD.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/alz.064325

Comparison of skin carotenoid content scores and dietary intake between cognitively normal older adults and older adults with Alzheimer’s Disease: A matched‐pair analysis

Amyloid‐β is a classical hallmark and risk factor for development of Alzheimer’s disease (AD). Observational data suggest that having higher body mass index (BMI) is associated with lower cerebral amyloid burden in cognitively normal adults. However, the influence of body composition on cerebral amyloid deposition has not been investigated. We investigated whether baseline body composition influences 1‐year change in cerebral amyloid in a sample enriched with older adults with elevated amyloid.

Higher body mass and fat composition are related to 1‐year cerebral amyloid accumulation in individuals with elevated risk for Alzheimer’ disease

Alzheimer's Disease (AD) is the most prevalent neurodegenerative disease, affecting approximately 6.5 million older adults in the United States. Development of AD treatment has primarily centered around developing pharmaceuticals that target amyloid-β (Aβ) plaques in the brain, a hallmark pathological biomarker that precedes symptomatic AD. Though recent clinical trials of novel drugs that target Aβ have demonstrated promising preliminary data, these pharmaceuticals have a poor history of developing into AD treatments, leading to hypotheses that other therapeutic targets may be more suitable for AD prevention and treatment. Impaired brain energy metabolism is another pathological hallmark that precedes the onset of AD that may provide a target for intervention. The brain Creatine (Cr) system plays a crucial role in maintaining bioenergetic flux and is disrupted in AD. Recent studies using AD mouse models have shown that supplementing with Cr improves brain bioenergetics, as well as AD biomarkers and cognition. Despite these promising findings, no human trials have investigated the potential benefits of Cr supplementation in AD. This narrative review discusses the link between Cr and AD and the potential for Cr supplementation as a treatment for AD. 

Creatine as a Therapeutic Target in Alzheimer's Disease

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Comparison of skin carotenoid content scores and dietary intake between cognitively normal older adults and older adults with Alzheimer’s Disease: A matched‐pair analysis

Higher body mass and fat composition are related to 1‐year cerebral amyloid accumulation in individuals with elevated risk for Alzheimer’ disease

Creatine as a Therapeutic Target in Alzheimer's Disease