Microalgae and exercise: from molecular mechanisms and brain health to clinical perspectives in the context of 3P medicine.

Microalgae and exercise: from molecular mechanisms and brain health to clinical perspectives in the context of 3P medicine - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Search Log in Primary site navigation Search Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice EPMA J . 2025 Mar 26;16(2):351–386. doi: 10.1007/s13167-025-00405-8 Microalgae and exercise: from molecular mechanisms and brain health to clinical perspectives in the context of 3P medicine Xuanyu Bo 1, ✉ Author information Article notes Copyright and License information 1 University of Glasgow, Gilmorehill, Glasgow, Scotland G128QQ UK ✉ Corresponding author. Received 2024 Oct 30; Accepted 2025 Mar 11; Collection date 2025 Jun. © The Author(s), under exclusive licence to European Association for Predictive, Preventive and Personalised Medicine (EPMA) 2025. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. PMC Copyright notice PMCID: PMC12106266  PMID: 40438495 Abstract Microalgae are emerging as innovative bioresources with diverse therapeutic applications, particularly in cardiovascular health, neuroprotection, anti-inflammatory, and antioxidant responses. These bioactive compounds effectively reduce inflammatory mediators, mitigate oxidative stress, and support mitochondrial health—critical factors in exercise performance, recovery, and chronic disease management. Notably, microalgae such as Spirulina and Chlorella exhibit promising biological activities in preclinical and limited clinical studies, including anti-inflammatory and neuroprotective effects. However, large-scale, randomized controlled trials (RCTs) remain scarce, limiting their clinical translation. Although preliminary evidence suggests potential benefits for sports performance, oxidative stress reduction, and cognitive function, most studies are small-scale, preclinical, or observational. Large, well-powered RCTs are needed to confirm their efficacy and safety. Within the framework of Predictive, Preventive, and Personalized Medicine (PPPM/3PM), this review explores microalgae’s potential in predictive diagnostics, targeted prevention, and individualized supplementation strategies. Despite promising findings, clinical application requires a cautious approach due to insufficient high-quality trials supporting microalgae-based interventions in medical practice. Future research should prioritize RCTs, pharmacokinetic studies, and long-term safety assessments to establish evidence-based guidelines for their use in health and disease management. Keywords: Predictive diagnostics, Targeted prevention, Personalized medicine, Predictive Preventive Personalized Medicine (PPPM / 3PM), Inflammation, Anti-inflammatory and neuroprotective effects, Microalgae, Spirulina, Mitochondrial health, Oxidative stress, Brain health, Sports performance Introduction Autotrophic microalgae are widespread, unicellular organisms capable of converting sunlight into chemical energy through photosynthesis. By fixing atmospheric carbon dioxide and utilizing water, microalgae generate hydrocarbons, forming biomass suitable for diverse commercial applications. They produce an array of bioactive compounds, including proteins, lipids, carbohydrates, carotenoids, polysaccharides, and vitamins [ 1 , 2 ]. These compounds find applications across the health, food, pharmaceutical, cosmetics, and aquaculture industries [ 3 ]. Additionally, microalgae contribute to environmental sustainability by absorbing contaminants such as heavy metals and radioactive compounds from water, making them an excellent candidate for wastewater treatment [ 4 ]. Among microalgae, Arthrospira (commonly known as spirulina ) stands out for its rich nutritional profile and bioactive properties. Spirulina , a blue-green microalga, has been consumed for centuries, particularly in North Africa and Mexico, for its high protein content (60–70% dry weight) and abundance of bioactive compounds, such as β-carotene, phycocyanin, γ-linolenic acid, vitamins, minerals, and essential amino acids [ 5 , 6 ]. Due to its anti-inflammatory properties, spirulina is widely utilized as a nutritional supplement and recommended for individuals with conditions such as arterial hypertension, insulin resistance, and diabetes [ 7 ]. However, despite promising findings, further large-scale RCTs are required to confirm its efficacy and establish standardized clinical recommendations. Similarly, Chlorella , a genus of green microalgae, contains a high protein content (59–70% dry weight) and is a rich source of essential amino acids, dietary fiber, and antioxidants, with applications in health and nutrition [ 8 , 9 ]. Under stress conditions, such as excessive light or nutrient limitation, Chlorella synthesizes triacylglycerols, further enhancing its nutritional value [ 10 ]. Microalgal bioactive compounds demonstrate significant potential in mitigating oxidative stress, hypertension, obesity, cardiovascular diseases, and cancer. Despite these advantages, their broader utilization in functional foods and medicine remains limited due to challenges like species diversity, cultivation variability, inefficient bioprocessing methods, and, most importantly, the lack of large-scale clinical evidence confirming their efficacy in human populations. Sensory factors, including odor and taste, also hinder their incorporation into food formulations. Nonetheless, the renewable nature and rapid growth rates of microalgae underscore their potential for advancing functional food development, provided these challenges are addressed through rigorous research [ 11 ]. Additionally, while initial clinical and preclinical studies suggest potential benefits, more robust clinical evidence is needed to substantiate therapeutic claims, particularly through well-powered RCTs. Recent studies highlight the neuroprotective roles of microalgae, particularly their ability to alleviate mental fatigue, modulate cerebral pressure, protect cerebrovascular integrity, and reduce oxidative stress [ 12 ]. Preliminary studies, mostly based on animal models and small-scale human trials, suggest that Spirulina may contribute to cognitive, motor, and language improvements. However, there is insufficient large-scale clinical evidence to support its therapeutic use in neurodegenerative conditions [ 13 ]. Furthermore, its supplementation can mitigate the behavioral, biochemical, and neuroanatomical impairments induced by stress and protect against exercise-induced hippocampal injury, highlighting its dual role in cognitive and physical health [ 14 ]. Nonetheless, these neuroprotective effects require further validation through high-quality human trials to confirm efficacy, dosage optimization, and long-term safety. In the evolving paradigm of the predictive, preventive, and personalized medicine (PPPM/3PM), microalgae have emerged as key players. Additionally, while initial clinical and preclinical studies suggest potential benefits, more robust clinical evidence is needed to substantiate therapeutic claims, particularly through well-powered RCTs. While Spirulina has demonstrated significant therapeutic potential, a comprehensive approach to health management requires the integration of multimodal and complementary therapies. In the context of the PPPM/3PM paradigm, the synergistic effects of combining microalgae supplementation with other evidence-based interventions are increasingly recognized. For example, emerging research suggests that combining Spirulina with polyphenol-rich diets, omega-3 fatty acids, and adaptogenic herbs may improve metabolic and inflammatory markers. However, clinical trials directly investigating these combined interventions remain limited, and further rigorous studies are needed. Furthermore, lifestyle interventions such as tailored exercise regimens and stress management techniques, including mindfulness-based cognitive therapy and yoga, can complement the effects of Spirulina by targeting neuroinflammatory pathways and enhancing mitochondrial resilience. Clinical evidence suggests that the integration of dietary interventions with behavioral modifications enhances long-term adherence and therapeutic outcomes, particularly in individuals at risk for metabolic and neurodegenerative disorders. By adopting a multimodal perspective that integrates nutritional, behavioral, and technological interventions, the therapeutic applications of microalgae can be expanded beyond their standalone benefits, offering a more comprehensive and individualized healthcare strategy. To address the growing need for individualized healthcare solutions, microalgae offer unique opportunities through their diverse bioactive profiles, enabling precise phenotyping and biomarker-based approaches. Recent advancements in omics technologies, including metabolomics and proteomics, facilitate the identification of microalgae-derived predictive biomarkers. These innovations contribute to risk stratification and early intervention strategies within the PPPM framework, optimizing health outcomes in sports medicine and neurodegenerative disorders. Leveraging these technologies enables microalgae to serve as key components of proactive healthcare, offering patient-specific solutions tailored to genetic predispositions and environmental exposures. Despite these advancements, the transition from laboratory-based findings to real-world clinical applications remains challenging due to the lack of large-scale human trials confirming predictive biomarker effectiveness. PPPM represents a transformative approach in modern healthcare, shifting the focus from reactive treatments to proactive interventions that anticipate disease risks, enable early diagnostics, and deliver tailored therapeutic strategies [ 15 – 17 ]. This paradigm is especially relevant for addressing multifactorial conditions, such as those influenced by chronic inflammation, oxidative stress, and mitochondrial dysfunction. By integrating data-driven diagnostics and individualized therapeutic algorithms, PPPM aims to improve health outcomes, enhance cost-effectiveness, and minimize adverse events [ 18 , 19 ]. Microalgae, such as spirulina and chlorella , align seamlessly with the PPPM paradigm. These bioresources offer multifaceted health benefits, including their ability to modulate oxidative stress, regulate inflammatory pathways, and enhance mitochondrial health—all of which are critical for personalized healthcare strategies. Mitochondrial medicine, a key component of PPPM, focuses on optimizing cellular energy production, mitigating oxidative damage, and enhancing resilience against metabolic and physical stressors. Recent studies have highlighted that bioactive compounds in microalgae, such as phycocyanin, γ-linolenic acid, and chlorophyll derivatives, play a vital role in supporting mitochondrial function and improving cellular recovery after exercise or injury [ 20 – 22 ]. Nevertheless, existing studies are primarily limited to short-term interventions, requiring extended-duration trials to evaluate long-term benefits and potential adverse effects. In the context of sports and exercise, the application of PPPM principles is particularly promising. Predictive diagnostics, enabled by advanced molecular profiling and phenotyping, can identify individuals at higher risk for exercise-induced injuries or oxidative stress. Microalgae supplementation can serve as a targeted preventive strategy to mitigate these risks by enhancing antioxidant defenses and reducing inflammation. Moreover, by tailoring supplementation regimens based on individual phenotypes, microalgae can optimize recovery, performance, and long-term health outcomes in both athletes and the general population [ 23 , 24 ]. The integration of microalgae into personalized healthcare extends beyond sports to encompass chronic disease management. The anti-inflammatory and neuroprotective properties of microalgae align with the broader goals of PPPM, particularly in addressing conditions such as neurodegenerative diseases, metabolic syndromes, and age-related cognitive decline. By modulating key molecular pathways, microalgae-derived compounds offer a natural and sustainable solution for preventive interventions and personalized treatments [ 25 , 26 ]. Early clinical studies indicate potential cognitive and metabolic benefits of Spirulina , though more high-quality, RCTs are required to confirm these findings. A randomized controlled trial examined the impact of Spirulina platensis supplementation on macrophage inhibitory cytokine-1 (MIC-1), oxidative stress markers, and anthropometric parameters in 56 obese individuals aged 20–50 years. Participants were divided into intervention and control groups, receiving either Spirulina platensis or a placebo daily for 12 weeks. The results indicated that Spirulina supplementation significantly reduced MIC-1 levels and appetite while enhancing superoxide dismutase (SOD) concentrations and improving anthropometric features. These beneficial effects were greater in the Spirulina group compared to the placebo group, highlighting the potential of Spirulina in obesity management by improving oxidative stress and regulating appetite [ 27 ]. Another randomized, double-blind clinical trial evaluated the antioxidant and metabolic effects of Spirulina liquid extract (Spirulysat®) in individuals with metabolic syndrome over a 12-week period. Spirulysat® supplementation was associated with a reduction in urinary isoprostanes, an indicator of oxidative stress, and improvements in lipid metabolism, including lower plasma triglycerides and increased HDL cholesterol levels. However, no notable change was observed in the oxidized LDL to total LDL cholesterol ratio. These findings suggest that Spirulysat® may contribute to the management of oxidative stress and metabolic disturbances in individuals with metabolic syndrome, supporting its potential role in preventive healthcare within the 3PM framework [ 28 ]. Despite these promising results, larger clinical trials with diverse populations are required to confirm these effects and establish standard treatment guidelines. This manuscript integrates microalgae’s therapeutic potential within the transformative framework of PPPM/3PM. By examining their roles in modulating mitochondrial health, oxidative stress, and inflammatory responses, the review highlights the capacity of microalgae-derived compounds to address multifactorial health challenges. This contribution is pivotal in facilitating early predictive diagnostics, such as identifying biomarkers for exercise-induced injuries or neurodegenerative risks, enabling stratification and personalized management of individuals. Furthermore, microalgae’s anti-inflammatory and antioxidant properties underline their utility in targeted prevention strategies, addressing critical gaps in managing chronic inflammation, cognitive decline, and exercise-induced damage. The manuscript also advances the personalization of medical interventions through tailored microalgae supplementation. By aligning supplementation protocols with individual phenotypic and genetic profiles, it emphasizes innovative approaches to optimizing athletic recovery, cognitive health, and chronic disease management. While current studies indicate promising applications, more rigorous, large-scale clinical trials are essential to substantiate these findings before clinical translation. Establishing high-quality, long-term studies is critical for determining optimal dosages, identifying potential contraindications, and confirming safety profiles for broader therapeutic use. These advancements position microalgae as a cornerstone in the shift from reactive to proactive healthcare, aligning with the objectives of PPPM to enhance resilience, improve health outcomes, and reduce healthcare costs. Through this comprehensive analysis, the review provides a critical foundation for future research, clinical translation, and global adoption of 3PM principles, reinforcing the need for a paradigm shift in modern medicine. Sources of data used English-language biomedical literature sources from Google Scholar, PubMed, Science Direct, and Scopus databases were analyzed for the topic-related items such as all the keywords listed above. The most recent scientific papers originated in July 2024 and were particularly taken into consideration for the final statement presented in the paper. Working hypothesis and rationale The increasing burden of oxidative stress, inflammation, and mitochondrial dysfunction in both athletic performance and chronic disease management highlights the urgent need for innovative approaches that align with 3PM. Microalgae, as bioresources rich in bioactive compounds such as phycocyanin, γ-linolenic acid, and chlorophyll derivatives, present a unique opportunity to address these challenges. However, while preclinical and preliminary clinical studies suggest beneficial effects, the clinical translation of microalgae-derived interventions remains limited due to a lack of large-scale RCTs confirming their efficacy and safety. This review hypothesizes that microalgae supplementation can bridge critical gaps in predictive diagnostics, targeted prevention, and personalized treatments by leveraging their biochemical versatility and therapeutic potential. Microalgae exhibit remarkable capabilities in modulating biomarkers associated with inflammation, oxidative stress, and mitochondrial dysfunction, all of which are critical in predicting risks for exercise-induced injuries, neurodegenerative conditions, and chronic diseases. Nonetheless, further well-designed RCTs are necessary to validate these claims before widespread clinical application. Predictive diagnostics play a crucial role in identifying individuals at risk for various health conditions and optimizing therapeutic interventions. Microalgae-derived bioactive compounds, including phycocyanin, carotenoids, polyunsaturated fatty acids (PUFAs), and antioxidants, hold significant promise as potential biomarkers for stratifying individuals based on their susceptibility to oxidative stress, inflammation, and metabolic dysregulation [ 29 , 30 ]. Recent studies have demonstrated the utility of phycocyanin and chlorophyll derivatives as indicators of systemic oxidative stress, which is a major contributing factor in chronic diseases such as cardiovascular disorders and neurodegeneration [ 31 , 32 ]. Elevated levels of these compounds in circulation can serve as early warning signals for individuals predisposed to oxidative damage, enabling timely intervention through lifestyle modifications and targeted supplementation. Furthermore, metabolomics profiling of microalgae-derived lipids and polysaccharides offers novel insights into metabolic resilience and susceptibility to disorders such as obesity and insulin resistance [ 33 , 34 ]. For example, recent studies indicate that the detection of specific fatty acid profiles, such as high levels of γ-linolenic acid, may be associated with enhanced anti-inflammatory potential and mitochondrial function, making it a valuable biomarker for predicting responses to nutritional interventions [ 35 ]. In the field of neurodegenerative diseases, microalgae-derived peptides and polyphenols have shown potential in predicting cognitive decline by modulating key pathways associated with neuroinflammation and synaptic plasticity [ 36 , 37 ]. These bioactive compounds, when measured through advanced diagnostic techniques such as metabolomics and proteomics, can provide valuable information on an individual’s cognitive health trajectory and guide personalized therapeutic strategies. Nevertheless, due to the complexity of neurodegenerative pathophysiology, additional long-term studies are required to confirm the predictive accuracy of these biomarkers and their relevance in clinical decision-making. Emerging technologies, such as multi-omics approaches (genomics, transcriptomics, proteomics, and metabolomics), provide a comprehensive perspective on the interplay between microalgae-derived bioactives and the host’s metabolic processes. These integrative methodologies allow for the identification of disease-specific biomarker panels, enabling early detection and targeted preventive interventions. However, despite promising preclinical findings, the clinical application of microalgae-based multi-omics biomarker discovery remains in its early stages, requiring large-scale human studies to establish reproducibility and clinical relevance. By leveraging multi-omics data, healthcare practitioners can assess the efficacy of microalgae supplementation in real time, adjusting therapeutic protocols to match dynamic biological responses. Additionally, AI-driven predictive modeling is transforming the landscape of personalized diagnostics by integrating large datasets from microalgae-based interventions. Machine learning algorithms can analyze complex interactions between biomarkers, genetic predispositions, and environmental factors to develop highly accurate risk prediction models. These models enhance the precision of microalgae supplementation regimens by providing tailored recommendations based on individual health profiles, thus reducing the risk of disease progression and improving therapeutic outcomes. However, these AI-based models require further validation through real-world clinical trials before they can be reliably incorporated into mainstream healthcare practices. Within the 3PM framework, microalgae-derived biomarkers can be effectively integrated into clinical practice by utilizing non-invasive diagnostic tools such as liquid biopsies and wearable health monitoring devices. These approaches facilitate continuous tracking of oxidative stress markers, inflammatory responses, and metabolic parameters, allowing healthcare providers to implement early interventions before the onset of clinical symptoms. This proactive approach not only improves patient outcomes but also reduces healthcare costs by focusing on disease prevention rather than treatment. Therefore, the integration of microalgae-derived biomarkers with cutting-edge diagnostic technologies such as multi-omics analysis and AI-based predictive models holds great promise for advancing personalized healthcare. These strategies enable precise risk stratification, timely intervention, and tailored supplementation plans, reinforcing the role of microalgae in shifting healthcare paradigms from reactive to proactive and personalized care. Despite the potential of these technologies, a significant gap remains in demonstrating their real-world feasibility, cost-effectiveness, and impact on patient outcomes in clinical setting. The ability of microalgae to influence these key molecular pathways underscores their potential role in predictive diagnostics, enabling the early identification of at-risk individuals and stratification of patients for targeted interventions. For instance, athletes prone to oxidative damage or individuals predisposed to chronic inflammatory conditions could benefit significantly from such predictive capabilities. In the context of 3PM, tailoring microalgae supplementation to individual phenotypic and metabolic profiles represents a crucial step in optimizing therapeutic efficacy. Patient stratification involves categorizing individuals based on genetic predisposition, metabolic status, and biomarker profiles to ensure precise and effective supplementation regimens. These approaches facilitate the identification of specific subpopulations that may benefit the most from targeted interventions, such as athletes, individuals with metabolic disorders, or those at risk for neurodegenerative conditions. Phenotyping strategies play a pivotal role in identifying individuals with varying inflammatory, oxidative stress, and metabolic profiles. For instance, individuals exhibiting elevated pro-inflammatory cytokine levels (e.g., IL-6, TNF-α) may benefit from microalgae-based interventions aimed at mitigating chronic inflammation and oxidative damage. In contrast, those with impaired mitochondrial function and metabolic inefficiencies could benefit from targeted supplementation to enhance cellular energy production and resilience against stressors. The integration of advanced diagnostic tools, such as wearable biosensors and personalized nutrition platforms, further enables continuous monitoring and adaptive supplementation strategies, aligning interventions with dynamic physiological changes. However, current patient stratification models lack the integration of large-scale clinical validation, necessitating future studies to refine their predictive accuracy and therapeutic applicability. The effectiveness of microalgae supplementation can also be modulated by gut microbiome composition, which influences the bioavailability and metabolism of microalgae-derived nutrients. Personalized gut microbiome profiling can help identify individuals who may require prebiotic or probiotic co-supplementation to optimize nutrient absorption and overall health outcomes. However, while preliminary studies suggest an interaction between the gut microbiome and microalgae bioactives, further mechanistic and interventional studies are needed to establish specific recommendations. Such precision-based approaches hold the potential to improve the efficacy of microalgae-based interventions in diverse populations, including aging individuals and those with chronic inflammatory conditions. Furthermore, machine learning algorithms and artificial intelligence-driven analytics can support the development of individualized supplementation plans by analyzing longitudinal health data and predicting optimal dosages based on lifestyle, environmental exposures, and genetic predispositions. By implementing stratification and phenotyping strategies, microalgae supplementation can transition from a generalized approach to a highly individualized therapeutic modality within the 3PM framework. In terms of targeted prevention, microalgae-derived compounds demonstrate potent anti-inflammatory, antioxidant, and neuroprotective effects. Spirulina , for example, reduces oxidative damage, inflammatory markers, and mitochondrial dysfunction, which are essential for preventing exercise-related injuries, neurodegenerative processes, and chronic pain. Similarly, Chlorella has shown promise in enhancing antioxidant defenses and supporting metabolic health, further solidifying the role of microalgae in preventing the progression of various pathophysiological conditions. These preventive properties are crucial for maintaining cellular health and mitigating the risks associated with oxidative and inflammatory stressors. However, these findings are largely based on small-scale studies, and their clinical implications require further investigation through larger, well-controlled human trials. Furthermore, the personalization of medical interventions can be effectively achieved through tailored microalgae supplementation. By aligning the supplementation strategy with individual health profiles, phenotypes, and activity levels, microalgae can optimize performance and recovery for athletes, while offering sustainable treatment strategies for patients with chronic conditions. This personalized approach not only enhances therapeutic efficacy but also minimizes adverse effects, paving the way for more effective and individualized healthcare interventions. For example, tailored supplementation regimens could be developed to optimize athletic recovery or to support cognitive and metabolic health in neurodegenerative or chronic disease contexts. This hypothesis is underpinned by the emerging evidence of microalgae’s role in mitochondrial medicine, which highlights their importance in energy metabolism, oxidative stress regulation, and cellular recovery. However, translating these mitochondrial benefits into mainstream medical applications requires further robust clinical trials to establish optimal dosages, safety profiles, and long-term effects. By integrating microalgae into the PPPM framework, healthcare can shift from reactive to proactive strategies, emphasizing cost-effective, individualized, and sustainable solutions. This approach aligns with the transformative vision of 3PM to enhance resilience against physical and cognitive stressors, improve health outcomes, and revolutionize modern medicine. Microalgae, therefore, emerge as powerful bioresources capable of catalyzing this paradigm shift in healthcare. Microalgae Definition and classification Microalgae are a family of microorganisms that share unicellular and eukaryotic characteristics while living with photosynthesis and in aquatic manner [ 38 ]. Looking back, we know that approximately 3.5 billion years ago, photosynthesis originated in cyanobacteria. Consequently, eukaryotes appeared after 1 to 1.5 billion years of prokaryotic evolution. By internalization or primary endosymbiosis, a lineage of eukaryotes, called the Archaeplastida, developed the ability to photosynthesis. Therefore, chlorophytes and rhodophytes which are green and red algae are produced as well as the glaucophytes. Meanwhile, secondary endosymbiosis in green or red microalgae, such as euglenoids and chromalveolates, led to the photosynthesis ability in other lineages of eukaryotes. Approximately 500 million years ago, all the terrestrial plants, embryophytes, originated from a signal lineage of the green algae, called charophytes. The mentioned endosymbiosis process has led to phylogenic diversity and consequently, metabolic diversity among microalgae. Several microalgae are capable of converting inorganic carbon (CO 2 ) into biomass (oxygenic photosynthesis); however, some lineages have lost this ability. The latter consumed organic carbon as their energy source, which enables them to grow independently to the light. Some other species, called mixotrophs, use both pathways to survive [ 38 ]. Despite their extensive metabolic diversity, translating the therapeutic potential of microalgae into clinical practice remains challenging. While preclinical studies indicate promising bioactivity, large-scale human trials assessing efficacy, safety, and bioavailability are still limited. This gap underscores the need for further research before microalgae-based interventions can be integrated into evidence-based medicine. Contents Microalgae generate various biochemical compounds, such as nucleic acids, carbohydrates, lipids, proteins, vitamins, and minerals. The composition of these compounds within each fraction is dependent on the strain of algae. Furthermore, how they interact with different environmental factors like light levels, temperature, nutrients, and growth stage make an impact on cellular content of each alga. Proteins Proteins are crucial in the structure and functioning of microalgal cells, serving as vital components in the membrane and light-capturing complex. They also include many catalytic enzymes essential for photosynthesis [ 57 ]. Research has compared the protein content of numerous species of microalgae to traditional protein sources [ 58 , 59 ]. Some microalgae species have been found to have remarkably high protein concentrations ranging from 42% to over 70% and up to 58% in some species of cyanobacteria and Chlorella vulgaris, respectively [ 47 ]. Microalgae are also rich in all the essential amino acids that mammals cannot produce themselves, with acceptable profiles similar to high-quality protein sources, such as lactoglobulin, egg albumin, and soy [ 57 ]. Until now, microalgal proteins have not been widely used in foods. The primary reason for this is the presence of non-protein elements, such as chlorophyll, which may impact the appearance and flavor of products based on microalgae. Additionally, the tough cell wall found in certain strains, particularly green microalgae like Chlorella and Tetraselmis, can hinder the extraction of proteins from within the cells. Using the entire biomass may also lead to reduced digestibility in humans. While microalgae proteins offer a complete amino acid profile comparable to conventional protein sources, their digestibility and functional properties in human nutrition require further validation through clinical trials to determine absorption efficiency and potential allergenicity. Carbohydrates Carbohydrates, categorized as mono-, oligo-, and polysaccharides, serve multiple roles within both structure and metabolism. They can be connected to proteins or lipids as seen in glycoproteins and glycolipids, with complex polysaccharides playing a significant role in forming cellular walls [ 39 ]. Furthermore, glucose and starch-like energy reserves are created by microalgae through photosynthesis, serving as primary carbon-containing products. The synthesis of polysaccharides varies across microalgae [ 40 ]. Cyanophytes specifically store glycogen while other species may produce semi-amylopectin [ 41 ]. Additionally, Chlorophyta create starch using glucose polymers like amylopectin and amylose [ 42 ]. Whereas, Rhodophyta generate floridean starch [ 43 ]. Diatoms, such as Bacillariophycae and Heterokontophyta , produce linear β (1,3) and β (1,6) linked glucose units, leading to chrysolaminarin formation [ 44 ]. During the exponential growth phase, certain diatoms can store as much as 30% of their dry weight as (1,3)-β- d -glucan, with cells able to amass up to 80% when facing severe nutrient restrictions. Conversely, a specific strain of Tetraselmis suecica was found to accumulate anywhere from 11 to 47% of its dry weight as starch when transitioning from nutrient-replete to nutrient-depleted conditions [ 45 ]. Despite being a potential source of advantageous carbohydrates, microalgae have had minimal utilization in food products as previously mentioned for microalgal proteins. On the other hand, microalgal polysaccharides are becoming increasingly essential in the cosmetic industry, serving as hygroscopic agents and antioxidants in various topical products [ 46 ]. Lipids Amidst the biochemical composition of microalgae, lipids have emerged as the focal point of extraction and commercial exploitation. However, the commercial value of polyunsaturated fatty acids, particularly omega fatty acids, has rendered them highly sought-after for nutraceutical and infant formula applications [ 47 ]. Lipids are essential structural components of plasma membranes, while neutral lipid bodies serve as secondary energy reserves after polysaccharide stores. The lipid fraction of microalgae comprises two main categories: (1) Neutral lipids: These include acylglycerols, free fatty acids, and carotenoids (e.g., β-carotene); (2) Polar lipids: These include various phospholipids and galactolipids. Microalgae typically exhibit an abundance of polar lipids during the exponential growth phase. Under stress conditions, notably during the stationary phase when nutrient availability becomes limited, triacylglycerols accumulate [ 48 , 49 ]. The lipid content of microalgal species varies considerably, ranging from 20 to 50% of the dry biomass. Extreme values between 1 and 70% have also been reported. Lipid production is species-specific and is strongly influenced by cultivation parameters, including growth stage, nutrient accessibility, salinity, light intensity, temperature, and pH [ 50 , 51 ]. Other derived compounds Pigments and fatty acids are currently the most commercially successful microalgal products [ 52 ]. Leading the market is β-carotene, extracted from the halotolerant green alga , Dunaliella salina [ 52 , 53 ]. Another notable carotenoid, astaxanthin, is produced by the green freshwater alga, Haematococcus pluvialis [ 54 ]. Astaxanthin commands a higher market value than β-carotene; however, its commercialization has been hampered by production challenges and a lack of established markets in the human nutraceutical sector [ 55 ]. PUFAs derived from microalgae constitute another lucrative commercial product [ 56 ]. Species such as Cryptothecodininum cohnii and Schizochytrium limacinum are cultivated heterotrophically in fermenters for the production of docosahexaenoic acid (DHA), which is a crucial component of infant formula [ 47 , 57 ]. Beyond carotenoids and PUFAs, microalgae hold considerable potential for further bioactive compound discovery, paving the way for the development of innovative natural products. Benefits Antibacterial activity Microalgal lipid complexes derived from Chlorella vulgaris and Arthrospira platensis possess antibacterial properties, particularly against Bacillus subtilis . The optimal inhibition zone was approximately 0.7 cm. Additionally, carbohydrate-rich complexes from C . vulgaris and A . platensis exhibited inhibitory effects against Bacillus subtilis and Escherichia coli , respectively, with inhibition zones ranging from 2.0 to 3.5 cm. Fourier transform infrared (FTIR) spectroscopy revealed the presence of functional groups, such as carbonyl groups, neutral lipids, glycolipids, and phospholipids in these complexes, contributing to their antimicrobial activity [ 58 ]. As evidenced by Shaima et al. [ 59 ], the microalgae extract from Chlorella sp . designated as UKM8-ME has exhibited considerable antibacterial efficacy. The minimum inhibitory concentrations of UKM8-ME ranged from 0.312 to 6.25 mg/mL. Cytotoxicity assessments conducted using the MTT assay revealed no adverse effects of the methanolic microalgae extracts on Vero cells. Gas chromatography-mass spectrometry (GC–MS) analysis identified 28 distinct compounds in UKM8-ME. The primary constituents included phenol, hexadecanoic acid, phytol, 9,12-octadecadienoic acid, and bicyclo heptane. These compounds have been associated with antimicrobial properties. Therefore, the methanol extracts derived from Chlorella sp. (UKM8) demonstrated promising antibacterial activity [ 59 ]. In the context of PPPM/3PM, these bioactive compounds can act as predictive tools for identifying bacterial resistance patterns and tailoring treatment strategies. Their cytocompatibility supports targeted and preventive applications, particularly in vulnerable populations. Microalgal-based therapies can be customized for specific bacterial infections, offering a safe, effective, and personalized solution for bacterial management. Although in vitro studies demonstrate antimicrobial activity, the clinical relevance of microalgae-derived antibacterial agents remains unexplored. Their potential application in treating bacterial infections requires further pharmacokinetic and clinical validation. Antiviral activity Several molecules with antiviral and antimicrobial properties have been found in cyanobacteria, such as Nostoc ellipsosporum-isolated cyanovirin N. This compound is able to make changes in the binding of human immunodeficiency virus (HIV) to CD + T cells [ 60 , 61 ]. Indeed, cyanovirin‐N exerts its antiviral effect against HIV through binding to the gp120, a viral spike protein, which is necessary for HIV to bind with its receptors in a human host [ 62 , 63 ]. The effectiveness of this antiviral compound has been also revealed in other types of viruses, such as feline immunodeficiency virus (FIV), herpes, and measles [ 62 ]. Regarding severe acute respiratory syndrome coronavirus‐2, cyanovirin‐N is also shown to bind with homotrimeric transmembrane spike glycoprotein and exerting antiviral roles. Another effective molecule with antiviral properties is lectin. It is found that lectin that is isolated from the cyanobacterium Oscillatoria acuminate suppresses herpes simplex virus type‐1 at doses as low as 20 ng mL −1 . It is implied that this lectin interferes with viral receptors since pre-treating cells before the infection with the virus is not effective [ 64 ]. Pre-treatment studies suggest lectin targets viral entry pathways, supporting its use as a preventive antiviral agent. In addition to the mentioned molecules, microalgae-isolated polysaccharides are also useful against viral infections, such as those isolated from Scenedesmus quadricauda , Chlorella saccharophila , Chlorella sorokiniana , and Micrasterias crux‐melitensis [ 65 ]. These compounds can be explored for their predictive potential in identifying viral susceptibilities and for tailoring antiviral strategies in personalized medicine frameworks. Their safety and bioavailability further make them promising candidates for preventive and targeted antiviral therapies. These compounds can be explored for their predictive potential in identifying viral susceptibilities and for tailoring antiviral strategies in personalized medicine frameworks. Their safety and bioavailability further make them promising candidates for preventive and targeted antiviral therapies. While these bioactive compounds demonstrate antiviral potential in laboratory settings, their pharmacodynamics, bioavailability, and efficacy in human infections remain largely untested. Advancing their development requires well-structured clinical trials to establish dosing, safety, and effectiveness. Antioxidant activity A study has been conducted by Coulombier and colleagues to test microalgae’s antioxidative abilities through four different methods in which 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azino-bis (3-éthylbenzothiazoline-6-sulphonique) (ABTS), oxygen radical absorbance capacity (ORAC), and thiobabituric acid reactive substances (TBARS) are used. Results have indicated that none of the investigated microalgae exhibit the ability to eliminate DPPH and ABTS free radicals. However, Chaetoceros sp., Nephroselmis sp., and Nitzschia A sp. possess the capacity to scavenge peroxyl radicals (ORAC), while Tetraselmis sp., Nitzschia A sp., and Nephroselmis sp. demonstrate an inhibitory effect on TBARS. The carotenoid composition of the studied microalgae conforms to expected patterns, with siphonaxanthin detected in Nephroselmis sp. emerging as a notable pigment. Analysis revealed that xanthophylls constitute the primary contributors to peroxyl radical scavenging capacity as measured by the ORAC assay. However, no correlation was observed between carotenoids and the inhibition of lipid peroxidation via the TBARS assay. Additionally, the findings suggest a substantial influence of light intensity on the antioxidant capacity of microalgae [ 66 ]. A randomized, double-blind clinical trial evaluated the effects of spirulina sauce (20 g/day, containing 2 g of spirulina ) on glycemic indices, lipid profiles, oxidative stress markers, and anthropometric parameters in patients with type 2 diabetes over 2 months. The intervention group experienced notable reductions in triglycerides, total cholesterol, LDL cholesterol, and waist circumference compared to the placebo group. A decrease in malondialdehyde (MDA) levels indicated reduced oxidative stress, and insulin sensitivity improved as reflected by increased QUICKI scores. However, no significant improvements were observed in fasting blood glucose, HbA1c, insulin levels, HOMA-IR, body composition, or total antioxidant capacity. Additionally, appetite control improved, with participants reporting reduced hunger and a marginal increase in fullness. These findings suggest that spirulina sauce may be beneficial for improving lipid profiles, oxidative stress, and appetite regulation in type 2 diabetic patients, although its effect on glycemic control remains inconclusive [ 67 ]. These findings underscore the influence of environmental factors, such as light intensity, on the antioxidant capacity of microalgae, which may help tailor personalized antioxidant therapies in predictive and preventive medicine. Although the research demonstrated improvements in oxidative stress and metabolic markers, the trial duration was limited, and broader RCTs with larger sample sizes are required to confirm long-term clinical benefits and assess potential risks. Microalgae and cognitive function Our neuronal and cognitive functions are prone to be damaged by a variety of factors and conditions including genetics, trauma, degenerative processes, etc. Accumulative evidence has implied that dietary factors are pivotal in maintaining our brain’s health. In the framework of PPPM/3PM, microalgae-based interventions hold significant potential for tailored approaches to cognitive health. By targeting neuroinflammatory, oxidative, and neurodegenerative pathways, Spirulina and Chlorella demonstrate promise as part of multimodal strategies tailored to individual needs. In this regard, different microalgae may also be beneficial for protecting our cognition against damage. Spirulina is one of these microalgae which manifests neuroprotective effects through inhibiting neuro-inflammation [ 68 ], decreasing oxidative stress [ 69 ], anti-amyloid activities (also summarized in Fig. 1 ). Fig. 1. Open in a new tab Antibacterial activity of spirulina In 2010, Bachstetter and colleagues has conducted an animal study on rats in order to determine if the Spirulina has any effects against acute systemic inflammatory insult of lipopolysaccharide (LPS) on proliferative potential of hippocampal neural progenitor cells and observed rats fed with 1% SP showed a reduction in LPS-induced decreases in stem/progenitor cell proliferation [ 68 ]. In a similar way, Patil et al. [ 70 ] used Spirulina -supplemented diet on 5-day-old rat pups which were treated with 2 mg/kg of LPS. They observed that LPS injection increases the expression of Interleukin-1 beta (IL-1β) and decreases glutathione synthesis, the γ-glutamylcysteine ligase catalytic subunit (γGCLc), Nrf2, and brain-derived neurotrophic factor (BDNF) while Spirulina treatment is able to reverse some of these effects and thereby, providing neuroprotection in cells of substantia nigra (SN) [ 70 ]. This evidence supports Spirulina ’ s role as a preventive intervention in neuroinflammatory damage, which could be tailored based on individual inflammatory profiles or oxidative stress biomarkers. Recent advances in neurophenotyping methodologies allow for a deeper understanding of how microalgae bioactives interact with specific cognitive biomarkers. Through neuroimaging techniques and personalized biomarker assessment, interventions can be tailored to individuals at risk of cognitive decline. For instance, phycocyanin’s modulation of neuroinflammation and oxidative stress can be specifically targeted in populations identified through phenotypic screening as prone to neurodegenerative conditions, thereby enhancing the precision and effectiveness of microalgae-based interventions. In another study, Patil, Matte [ 71 ] declared that feeding lactating mothers a Spirulina diet may help shield the brains of nursing pups from neuro-inflammation and weakened antioxidant defenses as a result of peripheral inflammation. This protective effect possibly occurs through a reduction in p38 activation and elevated levels of the antioxidant miRNA-146a [ 71 ]. Such findings highlight the predictive and preventive role of Spirulina , particularly in vulnerable populations such as neonates or individuals with inflammatory predispositions. Hwang and colleagues manage another interesting study [ 69 ] which used Three-month-old male senescence-accelerated prone-8 (SAMP8) mice for determining the effects of SP on memory and oxidative stress. They divided these mice into two groups and treated them with either 50 mg/kg BW or 200 mg/kg BW of Spirulina and detected that the amyloid β-protein (Aβ) deposition can be decreased in the hippocampus and whole brain of both groups in comparison to the control group. Furthermore, the levels of lipid peroxidation in the hippocampus, striatum, and cortex were notably decreased in both Spirulina groups [ 69 ]. The 200 mg/kg BW Spirulina group showed significantly higher catalase activity compared to the control group. Although glutathione peroxidase activity was notably elevated only in the cortex of the 200 mg/kg group when compared to the SAMP8 control group, SOD activity in all brain regions did not show significant differences among the groups. In conclusion, Spirulina platensis ( SP ) could potentially prevent memory loss by reducing Aβ protein accumulation, lessening oxidative damage, and primarily increasing catalase activity [ 69 ]. These findings further emphasize Spirulina ’ s capacity for personalized intervention in aging populations at risk for oxidative stress-induced cognitive decline. Clinical trials provide further evidence supporting the neuroprotective effects of Spirulina . A randomized, double-blind clinical trial evaluated the effects of Spirulina maxima 70% ethanol extract (SM70EE) on memory improvement in 80 older adults with mild cognitive impairment. Participants were randomized to receive either 1 g/day of SM70EE or a placebo for 12 weeks. Significant improvements were observed in visual learning, visual working memory, and verbal learning test scores in the SM70EE group compared to the placebo group. The treatment group also demonstrated enhanced brain-derived neurotrophic factor levels and antioxidant capacity, suggesting neuroprotective effects. No adverse effects were reported, and SM70EE showed potential for managing symptoms of dementia and Alzheimer’s disease [ 72 ]. A randomized, double-blind, controlled clinical trial evaluated the effects of spirulina supplementation (500 mg/day, twice daily for 12 weeks) on cognitive function and metabolic markers in 60 Alzheimer’s disease (AD) patients. Compared to the placebo group, spirulina intake led to noticeable improvements in Mini-Mental State Examination (MMSE) scores, reductions in high-sensitivity C-reactive protein (hs-CRP), and enhancements in glucose homeostasis by lowering fasting glucose, insulin levels, and insulin resistance. Additionally, spirulina supplementation increased insulin sensitivity. These findings highlight spirulina ’s potential to support cognitive and metabolic health in AD patients [ 73 ]. While these findings indicate potential cognitive benefits, additional trials with diverse populations and longer follow-up durations are needed to confirm their clinical applicability. Beyond Spirulina , other microalgae such as Chlorella also exhibit neuroprotective properties. Chlorella similarly prevents neuronal cellular damage by suppressing inflammation through suppressing PGE2, IL-6, TNF-α, cyclooxygenase-2 (COX-2), IL-1β, TGF-β1, and NF-κB [ 74 ]. Other than that, in vivo studies show that both spatial cognition and learning memory can be enhanced after chlorella treatment [ 74 ]. Chlorella ’ s ability to influence inflammatory pathways offers a preventive approach for individuals predisposed to neuroinflammation and cognitive impairment, aligning with personalized treatment strategies. Furthermore, another animal study shows that using Chlorella causes a boost in short-term memory in rats treated with Chlorella sorokiniana in comparison to the control group [ 75 ]. There were no notable differences in exploratory performance, locomotor activity, anxiety levels, or depressive tendencies between the two groups. However, there was a noteworthy decrease in social behavior in the rats treated with Chlorella sorokiniana , although there were no changes in aggressiveness. Furthermore, neurochemical analysis revealed that specific effects in different brain regions, with an increase in noradrenaline and serotonin levels seen in the hippocampus but not in the prefrontal cortex or striatum is the underlying mechanism by which Chlorella exerts these effects [ 75 ]. This suggests that personalized therapeutic approaches should carefully monitor behavioral and neurochemical responses to Chlorella supplementation. In another study, researchers administered Chlorella to mice to examine its impact on oxidative stress [ 76 ]. Results of this study indicated that the inclusion of Chlorella in the diet notably lessened oxidative stress levels and effectively halted cognitive decline as observed in both testing procedures. Additionally, the intake of Chlorella correlated with a reduction in the quantity of activated astrocytes within the brain of mitochondrial aldehyde dehydrogenase 2 (ALDH2) activity deficiency (DAL101) mice. These results imply that long-term Chlorella intake may hold promise in staving off the advancement of cognitive decline [ 76 ]. These findings support Chlorella ’ s role as a preventive and personalized intervention for individuals with mitochondrial dysfunction, offering a tailored strategy to mitigate cognitive decline. Chlorella has been shown to suppress neuroinflammatory markers, including PGE2, IL-6, TNF-α, and COX-2, thereby mitigating neuronal damage. In animal studies, Chlorella improved spatial cognition and memory by enhancing serotonin and noradrenaline levels in the hippocampus, while another study demonstrated its efficacy in reducing oxidative stress and activated astrocytes in models of mitochondrial dysfunction (50). These findings suggest Chlorella ’ s potential as an adjunct in mitigating neurodegenerative conditions. Additionally, emerging therapeutic options, such as algae-derived omega-3 fatty acids and polyphenols from other natural sources, have shown promise in neuroprotection by targeting oxidative stress and neuroinflammation pathways. Despite these promising findings, human clinical studies assessing Chlorella ’ s cognitive benefits remain scarce. More rigorous trials are required to evaluate its therapeutic potential in neurodegenerative conditions. Their mechanisms complement those of Spirulina and Chlorella , broadening the potential for dietary interventions in cognitive health. Microalgae supplementation, combined with personalized lifestyle modifications such as tailored exercise programs and stress management, supports a comprehensive, multimodal approach. By aligning these strategies with PPPM principles, microalgae-based therapies offer cost-effective, individualized solutions for cognitive health, shifting care from reactive to proactive and patient-centered interventions. Different microalgae and exercise: synergic effects There is a limited number of research investigating the potential impacts of microalgae supplementation on exercise-induced muscle damage, recovery, and performance in athletes and other people. However, we tried to gather evidence as much as possible. In this section, we review the effects of different microalgae including Chlorella , Spirulina ( Arthrospira ), and Tetraselmis as well as Isochrysis and Nannochloropsis on the efficacy of exercise and exercise-induced disadvantages (Also summarized in Table 1 ). Table 1. Studies investigating the effects of spirulina in exercise-induced damage, recovery, and performance Population Agent Subject(s) Dosage of supplementation Result(s) Reference(s) Athletes and trained subjects Spirulina Humans (rowers) 1500 mg of spirulina extract for 6 weeks Spirulina shows anti-inflammatory effects through decreasing the values of Treg/CTL after the exercise [ 77 ] Spirulina Humans 3 mg/day Spirulina shows anti-oxidant effects through decreasing serum β-carotene, α-tocopherol, and ascorbic acid [ 80 ] Spirulina Trained rats 500 mg/kg Spirulina decreases C-reactive protein levels and MDA and increases the antioxidant capacity [ 79 ] Spirulina Humans (rugby players) 5.7 g/day for 7 days Spirulina decreased creatine kinase, lipid peroxidation, and CRP [ 78 ] Other individuals Spirulina Humans (untrained females) – Spirulina lowers the levels of homocysteine [ 84 ] Spirulina Humans (untrained students) 3 weeks Spirulina causes a reduction in MDA, SOD, and GPx levels [ 83 ] Spirulina Humans (untrained males) 6 g/day of spirulina for seven days Spirulina reduces oxygen uptake and heart rate during exercise, and increasing oxygen uptake during at the time of fatigue [ 86 ] Spirulina Humans (obese men) 8 weeks Spirulina reduces weight and apelin and FBS and increases adipolin and ghrelin [ 87 ] Spirulina Humans (obese women) 8 weeks of 6 g/day The combination of Spirulina and training decreased fat free mass and increased IgA [ 88 ] Chlorella Mice 7 weeks of 0.05–0.15 g/kg/day CVE decreased the levels of BUN, CK, and LDH [ 89 ] Chlorella Mice 2 weeks Decreasing BUN and immobility time through enhancing immune function [ 90 ] Chlorella Rats 6 weeks of 0.5% chlorella powder Increasing performance through improving the expression of MCT1, MCT4, peroxisome proliferator-activated receptor γ coactivator-1α, LDH, phosphofructokinase, CS, and COX [ 91 ] Chlorella Rats 8 weeks of 0.5% chlorella powder in normal diet Chlorella decreases fasting blood glucose, insulin levels, and increases the insulin sensitivity index, PI3K, Akt phosphorylation, and GLUT4 translocation [ 92 ] Chlorella and Spirulina Humans – The combination of SP and CVE induces resting and post-workout myofibrillar protein synthesis [ 92 ] Tetraselmis chuii Humans – Tetraselmis chuii prevented declines in the isometric peak rate of force development [ 93 ] Tetraselmis chuii Rats 2.55 mg/kg/day Increasing TNF-α and IL-1b and malondialdehyde in rats [ 93 ] Open in a new tab Studies on athletes and trained individuals Anti-inflammatory effects In order to identify the effects of SP on immusnity and maximizing the physical activity, a study analyzed the performance of 19 members of polish rowing team and performed a 2000-m test on them before and after receiving SP supplementation [ 77 ]. In this double-blind study, T regulatory lymphocytes (Tregs) [CD4 + /CD25 + /CD127 − ], cytotoxic lymphocytes [CD8 + /TCRαβ + ], natural killer cells [CD3 − /CD16 + /CD56 + ], and TCRδγ-positive cells were determined as markers for post-exercise inflammation [ 77 ]. They concluded that Athletes in the supplemented group did not exhibit a rise in Treg count after exercise or a drop in Tδγ cell count after recovery (both of which were seen in the placebo group). Additionally, they had notably lower Treg/CTL values before and after exercising compared to the placebo group while the placebo group displayed a notable boost in Treg/ (NK + Tδγ + CTL) ratio after recovery [ 77 ]. However, no discernible improvement in participants’ performance was noted during a 2000-m rowing ergometer test [ 77 ]. Another study used C-reactive protein (CRP) as a marker for assessing the effects of Spirulina on inflammation and observed that the levels of CRP is not different before and after training in rats receiving this supplementation. However, in the placebo group, CRP rises immediately after training [ 78 ]. In this study, plasma creatine kinase (CK) was measured in order to confirm that exercise-induced muscle damage is inhibited after SP treatment which it was found that CK levels does not change before and after training in elite rugby players who received 5.7 g/day of SP [ 78 ]. Similarly, Brito and colleagues used CRP as a marker for inflammation and worked on trained rats. They also showed that concentrations of CRP can be decreased after 8 weeks of receiving 500 mg/kg of Spirulina in the trained group in comparison to the control group. The anti-inflammatory effects of Spirulina are attributed to its bioactive compound, phycocyanin, which inhibits COX-2 expression and suppresses the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. This inhibition occurs through the modulation of the NF-κB pathway, which is a critical regulator of inflammatory responses. Spirulina also downregulates reactive oxygen species (ROS) production by upregulating antioxidant enzymes like SOD and catalase, thereby reducing oxidative stress and inflammation caused by intense exercise [ 79 ] (Fig. 2 ). Fig. 2. Open in a new tab Antioxidant and anti-inflammatory activity of spirulina Antioxidant effects In another point of view, anti-oxidant effects of SP are also observed to be beneficial for decreasing the exercise damage in athletes. In this regard, a study compared the effects of 3 mg of SP supplementation and an antioxidant supplement on 90 male athletes aged between 15 and 21 and identified that the impacts of both of these agents are completely the same on serum antioxidant status [ 80 ]. They identified the effects of SP by measuring the levels of serum β-carotene, α-tocopherol, and ascorbic acid and observed lower levels of these markers in aerobic exercise and mixed exercise groups of individuals in their study ( p < 0.05) [ 80 ]. These results were also confirmed by another study which examined the levels of SOD, glutathione peroxidase, glutathione/glutathione disulfide ratio, oxidized low-density lipoprotein and F2α-isoprostanes (F2-Isop) as antioxidant markers in rugby players. In this study, spirulina was found to accelerate the return to baseline values regarding the fact that F2-isoprostanes and CK levels (24 h after training) were lower in rugby players who received SP ( p < 0.05) [ 78 ]. In addition, a study on rats also identified that receiving 500 mg/kg and 150 mg/kg of Spirulina supplementation after 8 weeks of training is able to cause a reduction in oxidative stress and MDA levels as well as an induction in the antioxidant capacity of these rats. The antioxidant effects of Spirulina stem from its ability to scavenge free radicals through its high content of phycocyanin, β-carotene, and other bioactive pigments. Phycocyanin interacts with free radicals to neutralize their effects, while its influence on Nrf2 pathways upregulates endogenous antioxidant defenses such as glutathione and SOD. These mechanisms collectively protect cells from oxidative damage, particularly during high-intensity exercise that generates excessive ROS. Beyond Spirulina , Isochrysis and Tetraselmis have demonstrated similar antioxidative effects in preclinical studies. Isochrysis contains fucoxanthin, a carotenoid with potent free radical-scavenging activity, while Tetraselmis exhibits high concentrations of PUFAs and phenolic compounds that contribute to its ability to reduce lipid peroxidation and enhance mitochondrial integrity under oxidative stress. These microalgae act on pathways such as mitochondrial biogenesis and repair, suggesting their role in sustaining energy metabolism during prolonged physical exertion [ 79 ]. Nonetheless, there are also some paradoxical results about the synergic effect of SP with exercise. For instance, assessing isokinetic leg strength and power, vertical jump, speed, and aerobic fitness in rugby players who have taken SP supplementation for 7 weeks shows that when comparing training only with training with Spirulina supplementation, no significant impact on leg maximal strength, power, or aerobic fitness can be detected. Elite rugby players who took Spirulina for seven weeks did not experience any improvement in body composition or physical performance. There was a minor, but non-significant, improvement in vertical jump and sprint performance among who received SP [ 81 ] (Fig. 2 ). Incorporating PPPM principles, microalgae supplementation offers a tailored approach to managing exercise-induced muscle damage and recovery. By using biomarkers of oxidative stress (e.g., MDA, CK) and inflammation (e.g., CRP, cytokines), predictive diagnostics can identify individuals at higher risk. Targeted preventive strategies, such as Spirulina, Isochrysis , or Tetraselmis supplementation, help mitigate inflammation and oxidative damage, enhancing recovery. Personalized regimens based on individual responses to exercise and nutritional status ensure a holistic and effective approach, advancing precision-based interventions in sports and exercise medicine. Recent clinical trials have explored the role of Spirulina platensis supplementation in mitigating exercise-induced oxidative stress and enhancing muscle performance. A study by Pappas, Tsiokanos [ 82 ] investigated the effects of Spirulina supplementation (6 g/day) on redox status, muscle performance, and muscle damage in 24 healthy, recreationally trained males subjected to eccentric exercise. The results showed no significant changes in redox status indices, such as total antioxidant capacity (TAC) and protein carbonyls (PC), between the Spirulina and placebo groups. Additionally, while delayed onset muscle soreness (DOMS) and eccentric peak torque (EPT) followed typical patterns of post-exercise muscle damage, Spirulina supplementation did not confer significant benefits in alleviating these markers. These findings indicate that Spirulina may not significantly impact muscle recovery or redox status following acute muscle-damaging exercise in this population. Another clinical trial by Lu, Hsieh [ 83 ] assessed the preventive effects of Spirulina platensis supplementation on skeletal muscle damage in untrained individuals. Over 3 weeks, 16 students consumed Spirulina alongside their normal diet and underwent incremental treadmill exercise. Results demonstrated significant reductions in plasma MDA levels, indicating decreased oxidative stress, while blood SOD activity increased significantly. Additionally, glutathione peroxidase (GPx) and lactate dehydrogenase (LDH) levels were significantly different between Spirulina and soy protein supplementation groups. Importantly, time to exhaustion (TE) was significantly extended in the Spirulina group, suggesting a protective effect against exercise-induced muscle damage and enhanced endurance performance. Studies on non-athlete individuals For a better understanding of the beneficial effects of Spirulina , investigating the outcomes of consuming this agent in non-athlete individuals is also essential. Nonetheless, the limited number of studies in this area is restricting our knowledge about the exact mechanisms and impacts of Spirulina . A study in 2006 used SP supplementation on 16 untrained students and examined the MDA, GPx, LDH, lactate, and SOD of their blood samples which were taken before and after exercise [ 83 ]. They recognized that lactate concentrations and time to exhaustion are higher in students who have received SP supplementation and the underlying mechanism is through causing a reduction in MDA, SOD, and GPx levels [ 83 ]. Another research performed on untrained individuals shows that lowering the levels of homocysteine is another mechanism by which the combination of SP and training decreases the levels of oxidative stress [ 84 ]. Homocysteine is known to take part in inducing the formation of ROS in a variety of organs and tissues [ 85 ]. A more recent study on 11 untrained men detected that 6 g/day of Spirulina seven days can increase exercise performance by two mechanisms: first decreasing oxygen uptake and heart rate during exercise and second increasing oxygen uptake at the time of fatigue. The underlying mechanisms of Spirulina ’ s effects on exercise performance are attributed to its high levels of phycocyanin, which enhances mitochondrial function and ATP production by modulating oxidative phosphorylation pathways. Additionally, Spirulina ’ s rich antioxidant profile, including carotenoids and phenolic compounds, scavenges ROS generated during physical exertion, thereby mitigating exercise-induced oxidative stress. This antioxidant action preserves cellular integrity and supports faster recovery, particularly in untrained individuals undergoing physical activity [ 86 ]. Most recent studies have tried to detect the favorable influences of SP in combination of training on obese men and women. In this regard, Mohammad and colleagues selected Sixty overweight and obese men (BMI > 25) ranging in age from 30 to 55 years. They concluded that overweight men may experience decreased weight and levels of apelin and FBS, while seeing greater levels of adipolin and ghrelin contents after undergoing 8 weeks of resistance training and taking Spirulina supplements at the same time [ 87 ]. Nobari et al. [ 88 ] tried high-intensity interval training (HIIT) and Spirulina supplementation on 30 obese women. In their study, they divided participants into three separate groups: placebo with training group, Spirulina group (SG), and combined group (CG). After giving of 6 g of Spirulina powder per day to the two later groups, they observed that CG significantly reduced fat free mass in participants ( p = 0.012) after training. Additionally, CG and SG showed significantly higher levels of IgA after 8 weeks ( p = 0.02 and p = 0.001, respectively). The synergistic effects of Spirulina with exercise in obese populations are linked to its ability to modulate adipokines such as apelin and adipolin, which play pivotal roles in lipid metabolism and insulin sensitivity. Spirulina also enhances the mitochondrial β-oxidation of fatty acids, thereby improving energy utilization during high-intensity workouts. These mechanisms not only support weight loss but also improve metabolic health, as evidenced by reductions in fasting blood glucose and increases in insulin sensitivity markers [ 88 ]. Other than Spirulina , Chlorella vulgaris ( CVE ) also appears to have some synergic effects with exercise. An and colleagues are one of the research groups who examined 0.05–0.15 g/kg/day of CVE on two groups of mice for 7 days and detected that the levels of BUN, CK, and LDH are lower in blood samples taken from mice which received CVE after a forced swimming test [ 89 ]. They suggested that the mentioned effects are probably increasing the stamina of mice after CVE consumption [ 89 ]. A similar study was conducted by Kim et al. [ 90 ] in 2010 and observed that after 14 days, the immobility time of the group treated with hydrolyzed CVE and malted barley was notably lower than that of the control group. Furthermore, there was a significant decrease in BUN of these mice. Additionally, for achieving a better understanding of the underlying mechanisms, they used this combination on human T cell line (Molt-4) and confirmed that CVE is able to enhance immune function through increasing interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) levels [ 90 ]. Affecting oxidative metabolism (in particular, lactate metabolism) is another valuable impact of CVE which helps increasing exercise performance. Horii et al. [ 91 ], in a study on 40 Sprague–Dawley rats, has shown that chlorella intake (0.5% chlorella powder in normal feed) for 6 weeks in combination with high-intensity intermittent exercise improved expression of monocarboxylate transporter (MCT)1, MCT4, and peroxisome proliferator-activated receptor γ coactivator-1α. This was accompanied by increased activities of LDH, phosphofructokinase, and other components of oxidative metabolism including citrate synthase and cytochrome-c oxidase in rats’ muscles. Also, they performance and maximal number of high-intensity interval exercise (HIIE) sessions were substantially raised when combining CVE with training. The mechanism underlying Chlorella ’ s effects is partly attributed to its chlorophyll content and polysaccharides, which enhance mitochondrial biogenesis and efficiency. Increased expression of MCT1 and MCT4 proteins facilitates lactate shuttling, preventing lactic acid accumulation during exercise. Chlorella also supports enhanced oxidative metabolism by upregulating key enzymes involved in the tricarboxylic acid (TCA) cycle and electron transport chain, leading to improved endurance and recovery [ 91 ]. Besides the animal studies, there is also a limited number of studies on humans including the one run by Horii et al. [ 92 ] examined the combination of aerobic exercise and CVE on rats with type 2 diabetes and found out that the consumption of Chlorella alongside aerobic training leads to a decrease in fasting blood glucose and insulin levels, as well as the total glucose area. This combination also increased the insulin sensitivity index while enhancing muscle phosphatidylinositol-3 kinase (PI3K) activity, protein kinase B (Akt) phosphorylation, and glucose transporter 4 (GLUT4) translocation levels. The synergistic effects of both chlorella intake and aerobic exercise resulted in a significant improvement compared to either intervention alone. These findings indicate that the combined approach holds greater potential in enhancing glycemic control through heightened activation of muscle PI3K/Akt/GLUT4 signaling in type 2 diabetic rats [ 92 ]. The most recent evidence in this field is a randomized, double-blind trial that examined plasma total and essential amino acid concentrations and myofibrillar protein synthesis rate in 36 individuals after giving them either SP alone or in combination with CVE and observed that consuming a single dose of algae-sourced SP and CVE leads to induction in resting and post-workout myofibrillar protein synthesis [ 92 ]. Last but not least, algae that is considered to enhance the outcome of exercise is Tetraselmis chuii which is a Marine phytoplankton. We only found one study about the synergic effects of this phytoplankton with exercise. In this human trial, 22 men and women participated and underwent a 14-day supplement loading phase before completing five consecutive days of intense resistance training [ 93 ]. The results of this study showed that Marine phytoplankton effectively maintained the isometric peak rate of force development, preventing notable declines when compared to the placebo. Furthermore, the concentration of salivary immunoglobulin A decreased significantly in the placebo group after the resistance training protocol, whereas it did not show the same decrease in the marine phytoplankton group [ 93 ]. Besides, there is an animal part in this study which was designed to uncover the underlying causes of Tetraselmis ’ s effect. In rats that received 5.1 mg/kg/day of Tetraselmis and underwent five consecutive days of intense resistance training, the levels of TNF-α were reported to be higher in both intramuscular and serum samples [ 93 ]. IL-1β and MDA are two other factors that were examined by Sharp and colleagues and were also detected to be increased in these rats. Tetraselmis chuii ’s effects may be linked to its bioactive compounds, such as PUFAs and carotenoids, which stabilize inflammatory markers like TNF-α and IL-1β during intense exercise. Its ability to modulate the hypothalamic–pituitary–adrenal (HPA) axis under physical stress may explain the observed improvements in resistance to fatigue and maintenance of muscle force [ 93 ]. Unfortunately, we could not find any other microalgae such as Nannochloropsis and Isochrysis to be examined either on humans or on animals. However, regarding the promising effects of microalgae, further studies are recommended. Microalgae supplementation, particularly Spirulina , Chlorella , and Tetraselmis , shows potential for improving exercise recovery and performance by modulating oxidative stress, inflammation, and muscle metabolism. However, current findings are largely based on preclinical and small-scale clinical studies, highlighting the need for larger, long-term human trials. Integrating PPPM principles, microalgae supplementation offers personalized strategies to optimize exercise recovery and performance. Predictive diagnostics, such as oxidative stress and inflammatory markers (e.g., MDA, CK, CRP), can identify individuals prone to exercise-induced damage, enabling early intervention. Targeted prevention through Spirulina , Chlorella , and Tetraselmis supplementation helps mitigate inflammation, oxidative stress, and mitochondrial dysfunction. Personalized regimens, considering individual metabolic needs, exercise capacity, and specific health conditions (e.g., obesity, diabetes), align with PPPM goals of tailored, holistic treatments, advancing the role of microalgae as a versatile solution in exercise and health management. Central sensitization and chronic pain mechanisms Chronic pain is a debilitating condition characterized by persistent pain that extends beyond the normal healing period, often associated with maladaptive changes in the central nervous system (CNS). A key underlying mechanism contributing to chronic pain is central sensitization, a pathological amplification of pain processing within the CNS that leads to heightened pain sensitivity and pain persistence even in the absence of ongoing tissue damage [ 94 ]. This process is implicated in a wide range of chronic pain conditions, including neuropathic pain, fibromyalgia, complex regional pain syndrome, migraine, osteoarthritis, and irritable bowel syndrome [ 95 ]. Central sensitization is primarily driven by increased excitability of dorsal horn neurons in the spinal cord and altered pain processing in higher-order brain structures such as the thalamus, amygdala, and anterior cingulate cortex [ 96 ]. As a result, affected individuals experience hyperalgesia, an exaggerated pain response to noxious stimuli, and allodynia, where normally innocuous stimuli elicit pain [ 97 , 98 ]. The persistent nature of central sensitization makes chronic pain refractory to conventional analgesic treatments and necessitates targeted therapeutic approaches to modulate underlying neurobiological mechanisms. Recent findings indicate that microalgae-derived bioactives may play a role in modulating these mechanisms, offering a novel avenue for chronic pain management. Preclinical evidence suggests that microalgae-derived bioactives influence neuroinflammatory pathways relevant to chronic pain, but their clinical efficacy remains to be confirmed in large-scale human studies [ 99 , 100 ]. At the molecular level, central sensitization involves enhanced excitatory neurotransmission, neuroinflammation, and impaired inhibitory control. A critical feature of this process is the excessive activation of glutamatergic pathways, which plays a pivotal role in the amplification of nociceptive signals. Sustained activation of NMDA ( N -methyl- d -aspartate) receptors on dorsal horn neurons leads to an influx of calcium ions, triggering intracellular signaling cascades that promote synaptic plasticity and long-term potentiation (LTP) of pain pathways [ 96 , 101 ]. This persistent synaptic strengthening results in an exaggerated response to peripheral stimuli, contributing to the transition from acute to chronic pain. Additionally, the hyperactivation of NMDA receptors promotes the release of ROS and nitric oxide, further exacerbating neuronal hyperexcitability [ 102 , 103 ]. Upon injury or repeated noxious stimuli, activated microglia secrete chemokines, including CCL2 and CX3CL1, that recruit immune cells and amplify inflammatory responses [ 104 ]. Neuroinflammation is another fundamental driver of central sensitization, involving the activation of glial cells, particularly microglia and astrocytes, in response to prolonged nociceptive input. Once activated, microglia release pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), which act on pain-processing neurons to enhance synaptic transmission and reduce pain thresholds [ 105 , 106 ]. These inflammatory mediators also potentiate NMDA receptor function, further sustaining central sensitization. Toll-like receptors (TLRs), particularly TLR4, play a key role in microglial activation and have been implicated in the maintenance of chronic pain states [ 98 ]. Additionally, astrocytes contribute to central sensitization by modulating extracellular glutamate levels, disrupting synaptic homeostasis, and sustaining neuroinflammatory responses [ 107 ]. A major contributor to pain amplification in central sensitization is the loss of inhibitory neurotransmission in the spinal cord. Under normal physiological conditions, inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA) and glycine regulate nociceptive transmission by suppressing excessive excitatory activity in the dorsal horn [ 108 ]. However, in chronic pain states, GABAergic and glycinergic inhibition is significantly diminished due to downregulation of inhibitory interneurons, decreased neurotransmitter release, and dysfunction of postsynaptic inhibitory receptors. This disinhibition leads to unchecked neuronal excitability and contributes to spontaneous pain, hyperalgesia, and allodynia [ 108 ]. Additionally, alterations in the descending pain modulatory system, which originates in the periaqueductal gray (PAG) and rostroventral medulla (RVM), play a crucial role in the persistence of central sensitization [ 109 ]. Normally, these descending pathways exert both facilitatory and inhibitory control over pain processing at the spinal level. However, in chronic pain conditions, there is an imbalance in these pathways, with a shift toward pain facilitation rather than inhibition [ 110 ]. This results in the amplification of nociceptive signals reaching the brain, perpetuating pain perception. Dysfunction of serotonergic and noradrenergic systems within the descending modulatory circuits further exacerbates central sensitization and contributes to the chronicity of pain [ 111 ]. Beyond neuronal mechanisms, sustained peripheral input also plays a role in maintaining central sensitization. Chronic inflammation, peripheral nerve injury, and persistent activation of nociceptors contribute to prolonged excitatory input to the CNS, reinforcing pain hypersensitivity. Neurogenic inflammation, characterized by the release of neuropeptides such as substance P and calcitonin gene-related peptide (CGRP), further sensitizes nociceptive pathways and promotes ongoing pain perception [ 112 ]. Additionally, maladaptive changes in the somatosensory cortex, including cortical reorganization and altered pain representation, contribute to pain chronification and its resistance to conventional analgesic treatments [ 113 ]. Understanding the pathophysiology of central sensitization has important clinical implications for the management of chronic pain. Several therapeutic strategies aim to target different aspects of this process. NMDA receptor antagonists such as ketamine have been explored for their ability to counteract NMDA receptor-mediated hyperexcitability and synaptic plasticity in chronic pain states [ 114 ]. Additionally, glial modulators such as minocycline and ibudilast have shown promise in reducing microglial-driven neuroinflammation and pain hypersensitivity [ 115 ]. Pharmacological approaches aimed at restoring inhibitory control, such as GABAergic agents and gabapentinoids (pregabalin and gabapentin), have been widely used to attenuate central sensitization [ 116 ]. Moreover, serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine and venlafaxine enhance descending pain inhibition and are effective in reducing central sensitization-related pain conditions [ 117 ]. Beyond pharmacological interventions, neuromodulatory and behavioral approaches play a crucial role in mitigating central sensitization. Techniques such as transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), and spinal cord stimulation (SCS) have demonstrated efficacy in altering pain-related neuroplasticity and restoring pain modulation [ 118 ]. Additionally, cognitive behavioral therapy (CBT), mindfulness-based stress reduction (MBSR), and graded motor imagery have been integrated into multimodal pain management strategies to address the psychological and behavioral dimensions of chronic pain [ 119 ]. Recent advancements in neuroimmune modulation and epigenetic regulation provide novel insights into the complex interplay between central sensitization and chronic pain, reinforcing the need for precision-based interventions in PPPM/3PM. Central sensitization is now recognized as a neuroimmune process involving reciprocal interactions between neurons, glial cells, and immune mediators, necessitating a broader therapeutic strategy that moves beyond traditional pharmacological and dietary approaches [ 120 ]. The persistent activation of microglia and astrocytes contributes to neuroinflammation and synaptic dysregulation, sustaining chronic pain states despite the absence of peripheral nociceptive input [ 121 ]. Advanced neuroimaging studies, including functional MRI (fMRI) and positron emission tomography (PET), have demonstrated alterations in brain regions involved in pain modulation, such as the insula, anterior cingulate cortex, and prefrontal cortex, highlighting the role of maladaptive neuroplasticity in central sensitization [ 122 , 123 ]. These findings underscore the need for multimodal therapeutic approaches that integrate targeted neuromodulation, epigenetic interventions, and regenerative medicine strategies alongside conventional pain management techniques. Epigenetic modifications, including DNA methylation and histone acetylation, play a pivotal role in pain chronification and treatment resistance. Chronic pain conditions are increasingly associated with aberrant epigenetic regulation of pain-related genes, leading to sustained hyperexcitability of nociceptive circuits [ 124 ]. Emerging therapies targeting epigenetic modifications, such as histone deacetylase (HDAC) inhibitors, have shown promise in reversing central sensitization by restoring normal gene expression patterns in pain pathways [ 125 , 126 ]. Additionally, non-coding RNAs, including microRNAs (miRNAs), are implicated in neuroinflammation and glial activation in chronic pain states. Recent research suggests that targeting pain-associated miRNAs could provide novel avenues for personalized pain management by modulating inflammatory responses and neuronal excitability [ 127 , 128 ]. Neuromodulatory approaches, including transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), have demonstrated efficacy in disrupting central sensitization and restoring pain modulation in chronic pain patients. These interventions can induce neuroplastic changes in pain-related brain circuits, providing a non-invasive and personalized treatment option for refractory pain conditions [ 128 – 130 ]. The integration of wearable biosensors and AI-driven predictive modeling further enhances the ability to personalize neuromodulatory therapies by tracking real-time pain fluctuations and physiological responses. Such advancements align with the principles of PPPM by shifting pain management toward a proactive, data-driven model that anticipates exacerbations and tailors interventions accordingly. Furthermore, stem cell-based therapies and regenerative medicine strategies are emerging as potential tools to counteract central sensitization and neuroinflammatory damage in chronic pain conditions. Mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) exhibit immunomodulatory and neuroprotective properties, with the ability to restore synaptic homeostasis and attenuate chronic pain [ 131 , 132 ]. Preclinical studies suggest that stem cell-based approaches could be particularly effective in reversing glial-driven neuroinflammation and restoring inhibitory neurotransmission, critical components in chronic pain persistence. These advancements collectively underscore the necessity of a PPPM-based approach to chronic pain management, moving beyond symptom-based treatments toward precision-targeted interventions informed by biomarker profiling, neuroimaging, and computational modeling. The integration of multi-omics data, neuroimmune modulation, and regenerative strategies provides a more comprehensive framework for predicting, preventing, and personalizing interventions for chronic pain sufferers, ultimately improving long-term treatment outcomes. Chronic pain is not a singular entity but a complex syndrome driven by diverse and overlapping pathophysiological mechanisms, including neuroinflammation, glial activation, impaired inhibitory control, and maladaptive neuroplasticity [ 133 , 134 ]. These interconnected processes contribute to pain persistence, treatment resistance, and the progression of central sensitization, underscoring the urgent need for precision-based interventions [ 94 , 135 ]. Conventional analgesic strategies often fail to address the heterogeneity of chronic pain conditions, necessitating a paradigm shift toward PPPM/3PM [ 136 , 137 ]. This approach moves beyond symptom management by integrating molecular profiling, neuroimaging biomarkers, and computational pain phenotyping to identify patient-specific pain mechanisms and tailor interventions accordingly [ 138 , 139 ]. Recent advancements in PPPM highlight the potential of biomarker-driven patient stratification to refine chronic pain management. By classifying individuals based on inflammatory signatures (e.g., IL-6, TNF-α, C-reactive protein), neurotransmitter imbalances, and functional neuroimaging data, clinicians can adopt more targeted therapeutic strategies [ 140 , 141 ]. Moreover, the implementation of machine learning algorithms in pain phenotyping enhances diagnostic accuracy, allowing for the development of personalized intervention protocols that account for individual variability in pain processing, neuroimmune interactions, and treatment responsiveness [ 142 ]. These approaches align with the core principles of PPPM by shifting chronic pain treatment from reactive, one-size-fits-all models to proactive, patient-specific frameworks. A key frontier in PPPM-based pain management is the integration of multimodal therapeutic strategies. Neuromodulation techniques such as TMS, VNS, and SCS offer promising avenues for modulating maladaptive pain circuits and restoring endogenous analgesic mechanisms [ 143 , 144 ]. When combined with anti-inflammatory pharmacotherapy and precision-based rehabilitation—including graded motor imagery, cognitive-behavioral therapy, and movement-based interventions—these neuromodulatory strategies provide synergistic benefits in mitigating central sensitization and pain hypersensitivity [ 145 , 146 ]. Additionally, the role of microalgae-derived bioactives in modulating neuroinflammation and oxidative stress presents an emerging research avenue that warrants further exploration, particularly in combination with advanced neuromodulation techniques. AI-driven predictive analytics and wearable biosensors further enhance the feasibility of these approaches, allowing for real-time monitoring of pain trajectories and dynamic treatment adjustments tailored to individual patient needs. Future research should prioritize the development of real-world patient stratification models that integrate multi-omics profiling, neuroimaging, and digital health technologies to refine chronic pain diagnosis and management. Additionally, large-scale clinical trials should explore the efficacy of combining microalgae-derived bioactives with neuromodulation and pharmacological interventions to optimize personalized treatment strategies. By leveraging PPPM principles, chronic pain treatment can transition from generalized, symptom-based management to precision-targeted therapies that improve long-term clinical outcomes and enhance patient quality of life. Thus, central sensitization is a key pathophysiological mechanism in chronic pain, involving excessive excitatory neurotransmission, neuroinflammation, impaired inhibitory control, and maladaptive pain plasticity. These changes contribute to persistent pain states that are often refractory to conventional treatments. Understanding the mechanisms underlying central sensitization provides valuable insights into novel therapeutic strategies, including pharmacological, neuromodulatory, and behavioral interventions, to improve pain management and enhance patient outcomes. Future research should continue to explore the complex interactions between neuronal, immune, and glial mechanisms in central sensitization and develop targeted, personalized approaches for chronic pain treatment. Despite promising preclinical evidence supporting the role of Spirulina and other microalgae in pain modulation, there is still a lack of large-scale RCTs confirming their clinical efficacy in chronic pain management. While some human trials suggest beneficial effects, most studies are limited in sample size and duration. A more precise look into the effects of microalgae on chronic pain Spirulina platensis , a well-known microalga, has demonstrated potential in mitigating central sensitization through its modulation of neuroinflammatory pathways. The primary bioactive pigment in Spirulina , phycocyanin, inhibits nuclear factor kappa B (NF-κB) activation, a critical transcription factor regulating pro-inflammatory cytokine expression [ 147 , 148 ]. NF-κB inhibition downregulates the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), leading to reduced NO and prostaglandin production, both known mediators of central sensitization [ 149 ]. Additionally, phycocyanobilin (PCB), a potent antioxidant found in Spirulina , activates the Nrf2/ARE pathway, enhancing antioxidant defenses and reducing oxidative stress in neuronal tissues [ 150 ]. By mitigating oxidative stress, PCB helps prevent mitochondrial dysfunction, a key contributor to the chronicity of neuropathic pain and neuroinflammation [ 151 ]. However, the translation of these molecular effects into clinical outcomes requires further validation through well-designed human trials. Animal models of chronic pain have shown that Spirulina supplementation suppresses neuroinflammatory markers such as TNF-α and IL-1β in the spinal cord, leading to reductions in neuropathic pain behaviors [ 152 ]. Spirulina treatment has also been associated with reduced gliosis and restoration of neurotrophic support through enhanced brain-derived neurotrophic factor (BDNF) levels, which are crucial for synaptic plasticity and neuronal repair [ 153 , 154 ]. Furthermore, clinical trials in neurodegenerative conditions, such as Alzheimer’s disease, have reported improvements in cognitive function and inflammatory profiles following Spirulina intake, underscoring its neuroprotective potential [ 72 ]. In addition to its anti-inflammatory properties, Spirulina modulates neurotransmitter systems that are dysregulated in chronic pain conditions. Studies have demonstrated that Spirulina increases serotonin and dopamine availability, contributing to pain modulation via descending inhibitory pathways [ 155 , 156 ]. Its anti-glutamatergic effects, achieved by reducing NMDA receptor hyperactivity, further contribute to attenuating central sensitization [ 157 ]. Mitochondrial dysfunction is increasingly recognized as a pivotal contributor to neurodegeneration, chronic pain, and exercise-induced oxidative stress. Microalgae-derived bioactives, such as phycocyanin and γ-linolenic acid, demonstrate promising potential in modulating mitochondrial resilience through Nrf2 activation, PGC-1α modulation, and ROS scavenging, positioning them as key players in mitochondrial medicine [ 24 , 158 ]. However, to fully integrate microalgae-based interventions into the PPPM/3PM paradigm, a comparative analysis with established mitochondrial-targeted therapies is essential. Coenzyme Q10 (CoQ10), resveratrol, and nicotinamide riboside (NR) are among the most widely studied mitochondrial enhancers, known to mitigate oxidative damage, enhance ATP synthesis, and stabilize mitochondrial membrane potential [ 159 , 160 ]. Comparative studies indicate that Spirulina ’ s phycocyanin exerts mitochondrial protective effects similar to CoQ10 by enhancing electron transport chain efficiency and reducing mitochondrial lipid peroxidation [ 161 ]. Furthermore, resveratrol, a polyphenolic compound, has been shown to activate SIRT1 and PGC-1α, promoting mitochondrial biogenesis—a mechanism that overlaps with Spirulina-induced Nrf2 activation [ 162 ]. Notably, emerging evidence suggests that microalgae-derived antioxidants may provide additional benefits by integrating both antioxidant and anti-inflammatory pathways, a feature less pronounced in conventional mitochondrial therapeutics [ 163 ]. While existing pharmacological interventions, such as NR and CoQ10, target mitochondrial bioenergetics and ROS neutralization, they often require synthetic formulation for optimized bioavailability. In contrast, microalgae-derived compounds offer a natural and potentially synergistic approach by addressing mitochondrial dysfunction at multiple regulatory levels, including oxidative phosphorylation, mitophagy, and inflammatory signaling. This underscores the need for comparative clinical trials evaluating microalgae-based interventions alongside established mitochondrial therapies to further validate their efficacy in neurodegenerative and chronic inflammatory conditions. However, clinical evidence confirming these mechanisms in human subjects remains limited, emphasizing the need for translational studies bridging preclinical and human research. Future research should emphasize integrating personalized mitochondrial biomarker assessments (e.g., ATP levels, mitochondrial DNA damage, MDA, and citrate synthase activity) to tailor microalgae supplementation for individuals at risk of exercise-induced oxidative damage, neurodegenerative disorders, and chronic pain syndromes. Such stratification would enable precision-targeted interventions within the PPPM framework, advancing microalgae-derived therapies from experimental models to clinical applications. Within the framework of 3PM, Spirulina supplementation can be tailored to individuals exhibiting biomarkers of neuroinflammation and oxidative stress. Personalized supplementation strategies can be developed by assessing specific inflammatory markers and mitochondrial dysfunction indicators, ensuring optimized therapeutic outcomes in chronic pain management [ 164 – 166 ]. Spirulina -derived bioactives present a promising avenue for mitigating the underlying mechanisms of central sensitization and neuroinflammation, offering a holistic, patient-centered approach to chronic pain treatment. Given its complexity, the management of chronic pain requires a paradigm shift towards predictive diagnostics, targeted prevention, and personalized therapeutic strategies, as emphasized by the PPPM/3PM that addresses the unique needs of each individual. Personalized interventions in chronic pain management Personalized interventions in chronic pain management focus on tailoring treatment plans to the specific characteristics of the patient [ 167 ]. This involves a comprehensive assessment that considers the individual’s medical history, pain experience, psychological state, lifestyle factors, and personal preferences. By understanding the unique aspects of each patient’s situation, healthcare providers can develop targeted strategies that are more likely to be effective. Such approaches can incorporate molecular profiling to stratify patients based on their susceptibility to neuroinflammation, oxidative stress, and central sensitization. For instance, biomarkers such as IL-6 and TNF-α can guide personalized supplementation with anti-inflammatory agents like SP . In the context of personalized medicine, biomarkers such as inflammatory cytokines (e.g., IL-6, TNF-α) and oxidative stress markers (e.g., MDA, SOD activity) may help identify individuals who are most likely to benefit from microalgae-based interventions. However, clinical trials integrating biomarker-based stratification are currently lacking, limiting the application of precision-targeted therapies. These strategies must also integrate innovative therapies and leverage evidence-based approaches to address the multifaceted nature of chronic pain and its underlying pathophysiology [ 168 ]. Such approaches can incorporate molecular profiling to identify high-risk patients and optimize supplementation dosages accordingly, ensuring more effective and individualized treatment strategies. Microalgae in the framework of PPPM/3PM Controlling chronic pain seems to be another advantageous feature of SP . Safakhah and colleagues are one of the research groups that tried to confirm this effect of SP [ 169 ]. They gathered 74 adults male Wistar rats, each weighing between 200 and 220 g, in this study. To induce neuropathic pain, a chronic constriction injury (CCI) was applied to the left sciatic nerve. SP was administered orally on a daily basis for 3 weeks. The assessment of mechanical allodynia and thermal hyperalgesia was conducted using Von Frey hairs and a plantar test device, respectively. Additionally, MDA levels and total antioxidant capacity (TOC) were measured in the serum through thio barbituric acid and the ferric reducing ability of plasma (FRAP) methods [ 169 ]. They detected that CCI of the sciatic nerve resulted in mechanical allodynia and thermal hyperalgesia both 2 and 3 weeks after the surgery. After 3 weeks of Spirulina treatment, there was a significant reduction ( p < 0.05) in the paw withdrawal response to mechanical and thermal stimuli compared to the control group. FRAP levels decreased significantly 3 weeks post-CCI, while MDA levels did not change, and Spirulina treatment notably restored FRAP levels closer to those of the control group. These findings suggest that SP could be integrated into personalized treatment plans for neuropathic pain by addressing oxidative stress, a key predictive biomarker for neuronal damage, aligning with the PPPM approach. The mechanisms underlying SP ’s effects in this study include its strong antioxidant activity and the ability to scavenge reactive oxygen species (ROS). By reducing oxidative stress markers and restoring antioxidant capacity, SP likely prevents neuronal damage associated with CCI-induced neuropathic pain. This effect could also be attributed to SP ’s phycocyanin content, which inhibits lipid peroxidation and promotes the stabilization of mitochondrial function, thereby protecting peripheral nerves [ 169 ]. Beyond Spirulina , cannabinoids have gained attention for their efficacy in chronic pain management. Cannabidiol (CBD) and tetrahydrocannabinol (THC) are the most studied cannabinoids, demonstrating analgesic and anti-inflammatory properties. CBD, in particular, has shown effectiveness in reducing glial activation and cytokine release, which are central to neuroinflammation and central sensitization. Clinical trials have also supported the efficacy of cannabinoids in managing neuropathic pain, fibromyalgia, and arthritis-related pain [ 170 , 171 ]. Furthermore, ketamine, an NMDA receptor antagonist, has emerged as a valuable option for treatment-resistant chronic pain. By blocking glutamatergic transmission, ketamine reduces hyperexcitability in the central nervous system, alleviating pain and addressing the core mechanisms of central sensitization. Low-dose ketamine infusions have been successfully employed in clinical settings for conditions such as complex regional pain syndrome and refractory neuropathic pain [ 172 ]. Another promising area of research involves peptide-based therapies, such as calcitonin gene-related peptide (CGRP) antagonists. These peptides are effective in treating migraine-related pain and are under investigation for broader applications in chronic pain syndromes. CGRP antagonists work by inhibiting the pathways involved in pain transmission and neuroinflammation, offering a targeted approach to managing pain [ 173 ]. Future research should investigate the synergistic effects of combining Spirulina with these pharmacological interventions to optimize pain management strategies. Another study also aimed to examine how SP influences various forms of pain and inflammation in rats [ 174 ]. Three groups of Long Evans rats, totaling 21 in each group and including both sexes, were utilized in the study. Group I received normal saline orally at a dose of 5 mL/kg/day for 21 days. Group II was given diclofenac sodium at a daily dose of 10 mg/kg for 7 days, while Group III was treated with SP at a dose of 400 mg/kg/day for 21 days. The impact of SP on pain was evaluated using the tail immersion test for nociceptive pain, the formalin test for nociceptive and inflammatory pain, and the Von Frey test for neuropathic pain. Additionally, the effects on inflammation were assessed through formalin-induced paw edema test [ 174 ]. SP demonstrated strong (statistically significant) pain-relieving effects in all three pain models (tail immersion, formalin, and Von Frey tests), along with anti-inflammatory benefits in the formalin-induced paw edema test. Notably, the anti-ulcer effects of SP were nearly the same as those of the negative control and significantly different from the positive control. In summary, these findings suggest that SP has potential in terms of analgesic, anti-inflammatory, and anti-ulcer properties. Such properties emphasize the potential for SP to be incorporated into tailored treatment regimens for patients with varying degrees of pain, ensuring personalized and holistic management. By integrating SP alongside standard anti-inflammatory treatments, this multimodal approach aligns with the targeted prevention pillar of PPPM. The analgesic and anti-inflammatory properties of SP in this study are likely mediated by its inhibition of cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS) pathways, resulting in a decreased production of prostaglandins and nitric oxide, which are key mediators of inflammation and pain. Furthermore, SP ’s ability to downregulate pro-inflammatory cytokines such as IL-6 and TNF-α contributes to its neuroprotective effects, especially in inflammatory pain models [ 174 ]. Jensen and colleagues used a randomized, double-blind, placebo-controlled study design in order to show this effect. They used a higher dosage of SP (despite previous studies which used 1 g of SP) 2.3 g/day of SP on 24 men and women for 2 weeks and observed that a notable decrease in chronic pain both at rest and during physical activity ( p < 0.05) can be achieved after SP consumption. The intake of SP demonstrated safety concerning anticoagulant activity markers and platelet activation status, along with prompt and effective relief of chronic pain [ 175 ]. The results of this clinical study highlight the role of personalized dosing strategies for SP supplementation, as patient-specific factors such as age, metabolic profile, and inflammatory markers may influence treatment outcomes, aligning with the personalization principle of PPPM. However, the study lacked long-term follow-up, and its small sample size limits the generalizability of its findings. Another study also tried to examined SP on mature male albino rats [ 176 ]. In their study, the formalin test was conducted in two stages after SP treatment: the initial stage took place during the first 10 min after the formalin injection, while the later stage was assessed between 15 and 60 min following the injection. They observed that rats treated with SP exhibited lower pain scores in both phases of the experiment compared to untreated diabetic rats. In the sodium salicylate group, however, the reduction in pain score was observed only in the second phase. Diabetic rats showed an intensified pain response following the formalin test. A notable pain-reducing effect was seen in control and diabetic rats that received SP treatment [ 176 ]. For a better understanding of the SP ’s mechanisms of action, Freitas et al. used SP on Male Swiss mice. They divided these mice into 3 groups: Spirulina (3–300 mg/kg, orally) receiving, indomethacin (10 mg/kg, orally) receiving, and a control solution (0.9% NaCl 10 mL/kg) group. They observed that Spirulina treatment significantly reduced pain-related behavior induced by formalin during the inflammatory phase, and this effect was notably blocked by an opioid-specific antagonist. Additionally, their findings suggest that the pain-relieving mechanisms of Spirulina seem to be linked to its influence on TRMP8 and TRPA1 channels, rather than TRPV1 or the glutamatergic system. The ability of SP to modulate TRP channels underscores its potential as part of a multimodal treatment approach that combines molecular-level targeting with personalized strategies. Such mechanisms offer promising alternatives to opioid-based therapies, advancing PPPM’s goals of safer, tailored treatment interventions. These findings emphasize SP 's multifaceted mechanism of action, which not only involves antioxidant and anti-inflammatory pathways but also the modulation of transient receptor potential (TRP) channels, specifically TRMP8 and TRPA1. These channels are known to play critical roles in pain sensation, and SP 's ability to modulate their activity offers a promising avenue for pain management without reliance on traditional opioid-based treatments [ 174 ]. In a neuroinflammation point of view, there are also some studies which tried to explain the mechanisms of action of SP. Piovan et al. [ 177 ] are one of the research groups which tried to investigate the impact of E1 on the secretion of IL-1β and TNF-α, the expression of iNOS, nuclear factor erythroid 2–related factor 2 (Nrf2), and heme oxygenase-1 (HO-1), as well as the activation of NF-κB, was examined in primary microglia. They concluded that prior to and shortly after treatment, non-toxic levels of E1 reduced the release of IL-1β and TNF-α, and diminished the excessive production of iNOS triggered by LPS. Additionally, E1 effectively inhibited the LPS-induced movement of the NF-κB p65 subunit into the nucleus and increased both the gene and protein levels of Nrf2, along with boosting the gene expression of HO-1 [ 177 ]. Another study also used BV-2 microglial cells and treated them with various concentrations of SP or its active component (C-phycocyanin (C-PC)) for 24 h. They also concluded that LPS enhanced the production of LDH and increased the levels of iNOS, COX-2, TNF-α, and IL-6 in BV-2 microglial cells. Conversely, water extract from SP and C-PC notably decreased LPS-triggered LDH release as well as the expression of iNOS, COX-2, TNF-α, and IL-6 mRNAs. Thus, Spirulina has the capacity to mitigate cytotoxicity and suppress the expression of inflammation-related genes in LPS-activated BV-2 microglial cells [ 148 ]. In another research, Koh et al. [ 178 ] examined the neuroprotective properties of SM70EE in relation to neurotoxicity caused by trimethyltin (TMT) in HT-22 cells. SM70EE was found to prevent the cleavage of poly-ADP ribose polymerase (PARP). Additionally, it diminished the production of ROS by reducing the activity of enzymes linked to oxidative stress. Furthermore, SM70EE enhanced the components of the BDNF/cyclic AMP-responsive element-binding protein (CREB) signaling pathways. Moreover, SM70EE inhibited acetylcholinesterase (AChE) activity. They also examined if SM70EE helps protect against cognitive impairments caused by scopolamine-induced neurotoxicity in mice by conducting behavioral assessments. The results showed that SM70EE lengthened the time taken to step through and shortened the escape latency time. As a result, their findings indicate that SM70EE might protect against TMT neurotoxicity by enhancing the activation of BDNF/CREB neuroprotective signaling pathways in neuronal cells [ 178 ]. These studies collectively underscore SP ’s potential as a versatile therapeutic agent that targets multiple pathways, including inflammatory cytokines, oxidative stress, TRP channels, and glial cell activation. Such a broad spectrum of mechanisms highlights the promise of SP as part of a multimodal approach to chronic pain and neuroinflammation management. The evidence provided demonstrates that SP holds significant potential as part of a PPPM/3PM-aligned approach to chronic pain and neuroinflammation management. By integrating predictive biomarkers, personalized supplementation strategies, and multimodal interventions, SP can offer tailored solutions for individuals based on their unique pain profiles and inflammatory status. Multimodal approaches in microalgae therapy: a holistic perspective While Spirulina and other microalgae demonstrate promising standalone therapeutic potential, a broader, multimodal approach is essential to fully harness their benefits. Combining Spirulina with other complementary interventions, such as dietary supplements, pharmaceuticals, physical activity, and lifestyle modifications, can offer synergistic effects that address multifactorial health conditions more comprehensively [ 104 , 179 ]. This holistic perspective aligns with the principles of 3PM, which emphasizes tailored interventions to optimize individual health outcomes. One key area where Spirulina can complement other interventions is in the realm of dietary supplementation. Combining Spirulina with omega-3 fatty acids, derived from sources such as fish oil or flaxseed, enhances its anti-inflammatory and neuroprotective effects, which are critical in cognitive health and cardiovascular function. Additionally, polyphenols from sources such as green tea, curcumin, and resveratrol have been shown to work synergistically with Spirulina ’s antioxidants, enhancing its ability to mitigate oxidative stress and support mitochondrial function. These combinations offer a comprehensive strategy for addressing chronic inflammation, metabolic dysregulation, and neurodegeneration [ 180 – 183 ]. Incorporating probiotics and prebiotics alongside Spirulina supplementation may further enhance its health benefits by modulating gut microbiota composition. The gut-brain axis plays a pivotal role in regulating inflammation and metabolic processes, and studies suggest that microalgae, when combined with probiotics like Lactobacillus and Bifidobacterium species, can support gastrointestinal health and immune function. This combination may help optimize nutrient absorption and promote a balanced inflammatory response, contributing to improved cognitive and metabolic outcomes [ 184 ]. Lifestyle interventions also play a crucial role in enhancing the therapeutic effects of Spirulina . Limited studies, primarily small-scale clinical trials and preclinical research, suggest that Spirulina and Chlorella supplementation may improve exercise performance, reduce oxidative stress, and enhance muscle recovery. However, these findings require confirmation through larger and more rigorous human trials [ 185 , 186 ]. Spirulina ’s bioactive compounds, such as phycocyanin and gamma-linolenic acid, can work in tandem with structured exercise regimens to support mitochondrial biogenesis and reduce inflammation. Similarly, incorporating stress management techniques such as mindfulness-based stress reduction (MBSR), yoga, and meditation can complement Spirulina ’s effects by further reducing cortisol levels and enhancing cognitive resilience[ 179 , 187 ]. Neuromodulation techniques, such as TMS, VNS, and deep brain stimulation (DBS), have shown promise in conditions characterized by central sensitization and neuroinflammation. These approaches modulate neural excitability and neurotransmitter release, providing relief in chronic pain and neurodegenerative disorders [ 146 , 188 ]. Emerging research suggests that Spirulina bioactives may reduce oxidative stress and promote neurotrophic support [ 189 , 190 ]. While neuromodulation therapies independently enhance neuronal resilience, the potential synergy between Spirulina supplementation and these interventions remains unexplored and warrants further investigation [ 191 ]. Pharmacological interventions can also benefit from the adjunctive use of Spirulina . For instance, nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids commonly used for chronic inflammatory conditions can have their dosage requirements reduced when used in combination with Spirulina , minimizing potential side effects [ 192 ]. The concurrent use of microalgae supplementation alongside pharmacological treatments targeting the NLRP3 inflammasome, cytokine pathways (IL-6, TNF-α), and neurotransmitter systems (GABA, glutamate) could improve treatment outcomes in patients with chronic pain, metabolic disorders, and neurodegenerative conditions [ 193 ]. Furthermore, microalgae can reduce the side effects of long-term pharmacotherapy by supporting liver function, enhancing detoxification pathways, and modulating gut microbiota composition. Moreover, Spirulina ’s neuroprotective properties have shown promise when combined with antioxidant drugs in the management of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. A key principle of PPPM is the integration of diverse therapeutic modalities to provide individualized and proactive healthcare. By leveraging predictive diagnostics, such as biomarker profiling and neuroimaging, healthcare practitioners can identify individuals who would benefit from a combination of microalgae supplementation and other therapeutic approaches. Tailoring multimodal strategies based on patient-specific data, including genetic predisposition, metabolic status, and lifestyle factors, ensures precision in therapeutic interventions and enhances overall health outcomes. Application of predictive biomarkers and patient stratification in clinical and sports settings As the integration of microalgae-based interventions progresses within PPPM, the application of predictive biomarkers and patient stratification becomes essential for optimizing clinical and sports-related strategies. This approach ensures a shift from generalized supplementation toward precision-based interventions tailored to an individual’s metabolic profile, oxidative stress levels, and inflammatory response. To effectively implement microalgae-derived bioactive compounds such as phycocyanin, polyphenols, and omega-3 PUFAs, a data-driven framework incorporating biomarker assessment, stratification, and continuous monitoring is required. In clinical settings, oxidative stress indicators such as MDA, SOD, GPx, and TAC are valuable tools for assessing systemic oxidative stress and mitochondrial function [ 194 ]. Similarly, inflammatory markers, including CRP, TNF-α, and IL-6, help identify individuals prone to chronic inflammation, cognitive decline, and metabolic disorders [ 195 ]. Stratification based on these biomarkers allows individuals to be categorized into low, moderate, or high-risk groups, enabling targeted supplementation strategies. For instance, those exhibiting elevated oxidative stress and mitochondrial dysfunction may benefit from high-dose Spirulina supplementation, which enhances mitochondrial biogenesis and modulates the NF-κB pathway to reduce inflammation [ 196 ]. Similarly, individuals with metabolic syndrome can be supported through polyphenol-rich microalgae to improve insulin sensitivity and lipid metabolism [ 197 ]. By periodically re-evaluating biomarkers every three to six months, interventions can be dynamically adjusted to align with an individual’s evolving physiological profile. In sports settings, integrating biomarker assessments provides a strategic advantage for athletes by optimizing performance, recovery, and injury prevention. Biomarkers such as CK, LDH, and F2-isoprostanes serve as indicators of muscle recovery, oxidative stress, and mitochondrial function, allowing stratification based on metabolic efficiency, training load, and inflammatory response [ 198 ]. Endurance athletes, who often experience sustained oxidative stress and mitochondrial strain, may benefit from omega-3 PUFA-rich microalgae to enhance recovery and cellular resilience [ 198 ]. Conversely, strength athletes experiencing frequent muscle damage may require Spirulina supplementation to regulate CK levels and expedite muscle repair. Real-time tracking using wearable biosensors and AI-driven predictive analytics further refines these personalized supplementation regimens, adapting interventions dynamically based on biomarker trends. Recent advancements in omics technologies, including metabolomics, proteomics, and transcriptomics, offer a more refined approach to precision-based interventions. Metabolomics enables the identification of individual metabolic responses to microalgae supplementation, helping to tailor interventions based on specific oxidative stress profiles, lipid metabolism, and mitochondrial function. Proteomics further enhances personalization by mapping protein expression changes in response to supplementation, offering deeper insights into inflammation modulation, neuroprotection, and exercise recovery. Additionally, transcriptomics allows for the identification of gene expression patterns associated with metabolic adaptations, enabling even more precise tailoring of microalgae supplementation to optimize physiological resilience. By integrating these omics-driven insights, clinicians and sports scientists can establish highly individualized supplementation strategies that optimize health outcomes, mitigate disease risks, and enhance athletic performance by aligning interventions with the body’s molecular adaptations. Recent advancements in omics technologies have significantly impacted sports medicine. For instance, the integration of genomics, transcriptomics, and metabolomics has enabled the optimization of physical performance and the prediction of sports-related injuries. Notable projects such as ELITE and GENE SMART are dedicated to discovering genomics-based biomarkers with substantial predictive power [ 199 ]. Metabolomics enables the identification of small-molecule metabolites that reflect the real-time physiological response to microalgae supplementation [ 200 ]. High-throughput techniques such as liquid chromatography-mass spectrometry (LC–MS) and nuclear magnetic resonance (NMR) spectroscopy allow for the profiling of oxidative stress markers, mitochondrial metabolites, and lipid metabolism pathways [ 201 , 202 ]. For instance, individuals exhibiting high MDA levels and altered glutathione homeostasis may benefit from Spirulina-derived phycocyanin, known for its potent antioxidant properties [ 203 ]. Furthermore, metabolomic analysis can help predict how individuals metabolize PUFAs from microalgae, ensuring that supplementation strategies are aligned with metabolic efficiency. Proteomics plays a crucial role in mapping protein expression changes in response to microalgae-derived bioactives. Using mass spectrometry (MS/MS) and high-resolution proteomic profiling, researchers can assess how microalgae supplementation influences inflammation markers such as TNF-α, IL-6, and CRP. Strength athletes experiencing elevated CK levels due to muscle strain may benefit from personalized Spirulina supplementation, which has been shown to modulate protein pathways involved in muscle recovery [ 78 ]. Additionally, proteomic insights can refine strategies for preventing cognitive decline by identifying neuroprotective proteins modulated by Chlorella supplementation [ 204 ]. Transcriptomics enables the identification of gene expression patterns associated with metabolic and inflammatory responses to microalgae supplementation. RNA sequencing (RNA-seq) can reveal specific genetic pathways activated by bioactive compounds, guiding personalized nutritional interventions. For example, individuals with genetic predispositions to oxidative stress-related conditions may require tailored microalgae supplementation strategies that upregulate genes involved in mitochondrial biogenesis and antioxidant defense mechanisms. Additionally, transcriptomic profiling can identify gene networks that regulate insulin sensitivity, allowing microalgae interventions to be customized for individuals with metabolic syndrome or type 2 diabetes. By integrating metabolomics, proteomics, and transcriptomics, a multi-omics approach provides a comprehensive understanding of an individual’s biochemical response to microalgae supplementation. AI and ML models further enhance predictive capabilities by analyzing large-scale omics datasets, refining supplementation regimens, and dynamically adjusting dosages based on real-time biomarker fluctuations. These technologies optimize the selection of bioactive microalgal compounds and anticipate physiological responses before clinical symptoms emerge. AI-powered predictive modeling enables precision in supplementation strategies for both clinical and athletic settings by accounting for oxidative stress, inflammation, and mitochondrial function. Deep learning algorithms enhance personalization by identifying interactions between genetic predispositions and environmental factors. Additionally, wearable biosensors, salivary biomarker analysis, and portable oxidative stress sensors support continuous monitoring, allowing for timely intervention adjustments and reducing the risk of suboptimal health outcomes. These advancements bridge the gap between cutting-edge omics research and practical clinical applications, ensuring highly personalized and responsive therapeutic strategies. Recent advancements in genetic predisposition analysis offer additional precision in tailoring microalgae-based interventions within the PPPM framework. Single nucleotide polymorphisms (SNPs) in genes associated with oxidative stress, inflammation, and mitochondrial function provide crucial insights into individual susceptibility to metabolic dysfunction and exercise-induced damage. For example, variants in the SOD2 gene (rs4880) influence mitochondrial antioxidant capacity, affecting an individual’s ability to counteract exercise-induced oxidative stress [ 205 ]. Similarly, SNPs in NRF2 (NFE2L2, rs6721961) modulate the endogenous antioxidant response, potentially determining responsiveness to phycocyanin-based supplementation for mitochondrial protection and neuroinflammation control. Polymorphisms in the PPARGC1A gene (rs8192678), which encodes PGC-1α, a master regulator of mitochondrial biogenesis, may help identify individuals who would benefit most from high-dose Spirulina supplementation to enhance mitochondrial efficiency and recovery [ 206 ]. Integrating genomic profiling with biomarker-based stratification enables a multi-layered precision approach, allowing clinicians and sports scientists to refine microalgae supplementation strategies based on both real-time physiological data and genetic predisposition. Future research should explore how gene-environment interactions influence individual responses to microalgae-derived bioactives, further advancing predictive diagnostics and precision supplementation in clinical and athletic settings. A crucial step in advancing the clinical application of microalgae-based interventions within the PPPM/3PM framework involves developing real-world implementation strategies that move beyond theoretical discussions into practical applications. One of the most pressing needs is the establishment of patient stratification models that allow for personalized supplementation approaches based on an individual’s inflammatory status, metabolic profile, and neurophysiological characteristics [ 146 ]. These models should integrate predictive biomarker assessments, such as cytokine levels (IL-6, TNF-α), oxidative stress indicators (MDA, TAC), and mitochondrial function markers, to identify subgroups of patients who would derive the most benefit from microalgae-derived bioactives. Such stratification is particularly relevant in sports medicine and chronic pain management, where inter-individual variability significantly influences treatment efficacy. In addition to biomarker-driven patient stratification, omics-based diagnostics—including metabolomics, proteomics, and transcriptomics—offer unprecedented insights into how microalgae supplementation influences biological pathways at the molecular level. Metabolomic profiling can reveal personalized responses to bioactive compounds, identifying specific metabolic signatures that correlate with improved mitochondrial function, reduced neuroinflammation, or enhanced muscle recovery. Proteomic analyses can track changes in protein expression related to anti-inflammatory and neuroprotective effects, while transcriptomic approaches help uncover gene expression changes linked to pain modulation and exercise adaptation. By integrating these multi-omics techniques, clinicians and sports scientists can develop precision-based intervention protocols that maximize therapeutic efficacy while minimizing variability in treatment response. Furthermore, the integration of digital health technologies—including AI-driven predictive modeling and wearable biosensors—can enhance the real-world applicability of PPPM strategies. AI-based algorithms can analyze large datasets from omics profiling, physiological markers, and lifestyle factors to generate personalized supplementation plans for individuals based on their unique biochemical and genetic predispositions. Wearable biosensors capable of tracking heart rate variability (HRV), oxidative stress levels, and inflammatory markers in real time provide continuous feedback on an individual’s physiological state, enabling dynamic adjustments in microalgae-based interventions. These technologies have significant implications for sports performance optimization and chronic pain management, allowing for real-time monitoring and early detection of physiological stressors that could be mitigated through targeted, personalized supplementation. By implementing these real-world PPPM strategies, microalgae-based interventions can move beyond generalized supplementation toward precision-targeted therapies tailored to individual needs. Future research should focus on integrating these methodologies into clinical and sports settings, refining stratification criteria, and validating omics-based approaches through well-designed, large-scale studies. These advancements will be essential for establishing microalgae as a viable component of predictive and personalized healthcare, ensuring optimized patient outcomes and improved long-term efficacy. By bridging predictive diagnostics, patient stratification, and dynamic supplementation strategies, microalgae supplementation can be seamlessly integrated within the PPPM framework. This approach ensures precise, evidence-based interventions that enhance health outcomes, optimize athletic performance, and improve long-term resilience against oxidative and inflammatory stressors. The application of these strategies forms the foundation for the multimodal approaches discussed in the subsequent section, where microalgae therapy is further examined in conjunction with other complementary interventions for a holistic, patient-centered healthcare model. Expert recommendations and outlook Microalgae, with their diverse bioactive compounds, present unique opportunities for innovation in the fields of exercise medicine, neuroprotection, and chronic disease management, especially when integrated within the framework of PPPM/3PM. Based on the current review, their potential extends beyond general health benefits, offering practical applications that address key challenges in modern healthcare. Despite encouraging preclinical evidence and small-scale clinical trials, the translation of microalgae-based interventions into widespread clinical use remains limited by the absence of large, long-term RCTs assessing their efficacy and safety across diverse populations. Current findings suggest beneficial effects on oxidative stress, inflammation, and metabolic regulation; however, additional high-quality research is required to confirm these effects in well-defined clinical settings. Future research should explore whether microalgae-derived compounds, such as phycocyanin and γ-linolenic acid, can serve as reliable biomarkers of mitochondrial dysfunction, oxidative stress, and inflammation. Currently, their predictive role remains largely hypothetical and requires rigorous clinical validation. These biomarkers can provide critical insights into the risk profiles of individuals, enabling the anticipation of health challenges before clinical symptoms manifest. This predictive capacity is especially vital in fields like sports medicine, where understanding susceptibility to injuries or fatigue could transform athlete management strategies. While microalgae supplementation presents promising therapeutic potential, it is essential to establish comprehensive clear dose–response relationships and assess long-term safety to optimize its clinical utility and ensure public health benefits. Recent preclinical and clinical studies have demonstrated the potential health benefits of microalgae-derived bioactive compounds, emphasizing their antioxidant, anti-inflammatory, and metabolic regulatory properties. However, understanding their precise dose–response relationships is critical to optimizing therapeutic efficacy and ensuring safety. Dose-dependent effects have been observed in several studies, where moderate doses of Spirulina and Chlorella supplementation led to significant improvements in oxidative stress markers, lipid profiles, and inflammatory responses. In contrast, excessive intake did not yield proportional benefits and, in some cases, resulted in gastrointestinal discomfort or oxidative imbalances. Recent RCTs suggest that moderate doses (e.g., 1–2 g/day) of Spirulina significantly enhances antioxidant capacity and immune function, whereas higher doses (> 5 g/day) may lead to pro-oxidant effects and diminished efficacy. Long-term safety assessments remain crucial for the sustained use of microalgae-based interventions. While short-term clinical trials indicate favorable outcomes with minimal adverse effects, prolonged exposure necessitates careful monitoring to evaluate potential risks, including heavy metal accumulation, allergic reactions, and interactions with conventional medications. Preclinical toxicology studies have provided valuable insights into the safe upper limits of microalgae consumption, suggesting that chronic administration within recommended dosage ranges does not elicit significant hepatotoxicity or nephrotoxicity. Nevertheless, the variability in microalgae composition due to cultivation conditions underscores the need for stringent quality control measures and standardized extraction processes to ensure batch-to-batch consistency. Although microalgae have demonstrated potential therapeutic applications, many of the claims in this manuscript are based on small-scale clinical trials or preclinical studies. Larger, multi-center RCTs are urgently needed to validate their efficacy across diverse populations and health conditions. Future research should focus on establishing comprehensive dose–response models by integrating advanced pharmacokinetic and pharmacodynamic studies, enabling personalized supplementation strategies tailored to individual metabolic profiles. Investigating the long-term safety and efficacy of microalgae supplementation through well-defined clinical endpoints, including biomarkers of systemic inflammation, oxidative stress, and metabolic health, will provide stronger evidence for their clinical utility. Additionally, regulatory frameworks must be established to ensure the standardization and quality control of microalgae-based supplements for human consumption. Moreover, the targeted preventive applications of microalgae deserve further exploration. Their ability to modulate inflammatory pathways and enhance mitochondrial health positions them as effective supplements for individuals prone to exercise-induced damage, neuroinflammatory conditions, or metabolic disorders. Preventive healthcare strategies should integrate microalgae into dietary interventions, particularly in populations at risk for cognitive decline or chronic pain. This approach can be scaled for broader demographic reach while maintaining the specificity required for effective outcomes. By tailoring microalgae supplementation to individual needs and phenotypic profiles, healthcare practitioners can refine prevention strategies that are not only cost-effective but also ecologically sustainable. Personalized treatment protocols leveraging microalgae compounds represent the next frontier in precision medicine. Future studies should focus on refining personalized microalgae-based interventions by integrating epigenetic profiling and personalized gut microbiome analysis. Emerging evidence suggests that individualized responses to microalgae supplementation can be significantly influenced by gut microbiota composition, necessitating tailored formulations for maximum efficacy. Additionally, artificial intelligence-driven analytics can help optimize supplementation strategies by predicting patient-specific responses based on historical health data, further aligning with the 3PM goals of cost-effective and individualized healthcare solutions. These protocols can be customized based on genetic, epigenetic, and environmental factors to address diverse health conditions. For instance, personalized microalgae formulations could enhance recovery and performance in athletes, counter oxidative stress in patients with chronic conditions, or mitigate neurodegenerative processes in aging populations. Integrating advanced phenotyping and molecular profiling tools into clinical settings will further enhance the personalization of these interventions, ensuring optimal therapeutic outcomes. While preliminary clinical trials support the therapeutic potential of microalgae-derived bioactives, existing RCTs present inherent limitations that must be addressed to substantiate their clinical applicability. Many studies investigating microalgae supplementation have small sample sizes, short follow-up durations, and variability in participant characteristics, which may limit the generalizability of findings. Additionally, heterogeneity in study designs, including variations in microalgae strains, dosage regimens, and outcome measures, complicates direct comparisons and meta-analyses. A notable challenge in microalgae research is the lack of large-scale, multi-center RCTs that would provide more robust evidence for their efficacy and safety across diverse populations. While some clinical trials demonstrate beneficial effects on oxidative stress, inflammation, and metabolic health, others report modest or inconclusive outcomes, likely due to differences in study methodology, participant adherence, and dietary confounders. Furthermore, long-term safety assessments remain scarce, particularly regarding potential interactions with conventional medications, bioavailability concerns, and cumulative effects of prolonged supplementation. To strengthen clinical translation, future studies should focus on well-powered, placebo-controlled RCTs with standardized protocols that assess dose–response relationships, long-term outcomes, and potential contraindications. The incorporation of biomarker-driven stratification (e.g., inflammatory markers, mitochondrial function assays, and gut microbiome profiling) could refine patient selection criteria and enhance the personalization of microalgae interventions within the PPPM/3PM framework. By explicitly acknowledging these current research limitations, this manuscript aims to provide a balanced perspective, ensuring that therapeutic claims are grounded in available evidence while emphasizing the need for further validation through rigorous clinical trials. While microalgae-derived bioactives hold promise in mitigating inflammation, oxidative stress, and mitochondrial dysfunction, a comprehensive therapeutic strategy should extend beyond dietary and lifestyle modifications. Integrating pharmacological, regenerative, and technology-driven approaches enhances their clinical utility, particularly in the context of precision-based medicine. Recent research suggests that combining microalgae supplementation with targeted pharmacological agents can optimize mitochondrial health, cognitive resilience, and metabolic function. Recent studies have explored the synergistic effects of combining microalgae supplementation with targeted pharmacological agents to enhance mitochondrial health, cognitive resilience, and metabolic function. For instance, the co-administration of microalgae-derived compounds with polyphenolic substances such as resveratrol can be investigated for their potential to improve mitochondrial function and metabolic health [ 207 ]. Similarly, combining microalgae with NAD + precursors like NR or nicotinamide mononucleotide (NMN) may improve cellular energy metabolism and counteract oxidative stress-induced mitochondrial dysfunction [ 208 ]. Emerging evidence also supports the potential of adaptogenic herbal extracts, including Rhodiola rosea, ginseng, and ashwagandha, to regulate stress-responsive pathways [ 209 ], suggesting that their concurrent use with Spirulina could optimize HPA-axis modulation and neuroendocrine resilience. In neurocognitive applications, supplementing microalgae-derived antioxidants with nootropic compounds such as acetyl- l -carnitine, phosphatidylserine, and alpha-GPC [ 210 ] may enhance synaptic plasticity, cognitive performance, and memory retention, particularly in individuals experiencing cognitive fatigue due to prolonged physical or mental exertion. Beyond pharmacological co-interventions, regenerative medicine approaches are emerging as a complementary strategy to harness microalgae-derived bioactives for tissue repair and neuroregeneration. Exosome-based therapies offer a promising avenue where stem cell-derived exosomes can be engineered to carry microalgal bioactives such as phycocyanin, DHA, and polyphenols, thereby facilitating targeted tissue regeneration and anti-inflammatory effects in neurodegenerative diseases, sports injuries, and metabolic disorders [ 68 ]. Furthermore, bioengineered hydrogels infused with microalgae-derived antioxidants may enhance localized delivery to damaged tissues, offering potential applications in post-exercise muscle recovery and neuroprotection [ 24 , 211 ]. Additionally, preconditioning MSCs with microalgae-derived compounds may enhance their anti-inflammatory, neuroprotective, and mitochondrial-supportive properties, positioning them as an adjunctive strategy in regenerative medicine [ 212 ]. The integration of artificial intelligence (AI), digital health technologies, and biosensors further expands the therapeutic potential of microalgae-based interventions. AI-driven predictive analytics can refine supplementation regimens by analyzing biomarker fluctuations over time, allowing for dynamic dose adjustments based on real-time physiological data [ 212 , 213 ]. Wearable biosensors capable of continuously tracking heart rate variability (HRV), oxidative stress markers (e.g., MDA, TAC), and inflammatory cytokines (e.g., IL-6, CRP) enable personalized supplementation strategies tailored to an individual’s metabolic demands [ 213 ]. Moreover, advancements in saliva- and sweat-based diagnostic devices provide a non-invasive method for monitoring oxidative stress levels [ 213 , 214 ], facilitating precision-targeted microalgae interventions in both clinical and sports performance settings. By integrating AI-powered monitoring tools with multi-omics profiling, including metabolomics, proteomics, and transcriptomics, healthcare practitioners can predict an individual’s response to microalgae supplementation, enabling proactive and highly personalized healthcare strategies. Future research should prioritize large-scale clinical trials evaluating these multimodal approaches to validate their efficacy and safety across diverse populations. While existing evidence supports the synergistic benefits of combining microalgae with pharmacological agents, regenerative therapies, and AI-driven monitoring tools, further studies are necessary to establish standardized protocols for personalized interventions. By bridging the gap between preclinical promise and clinical application, these integrative strategies position microalgae-based therapies at the forefront of modern PPPM/3PM, offering a holistic, multidimensional approach to optimizing health outcomes. Looking ahead, the integration of microalgae into healthcare requires a multidisciplinary effort involving researchers, clinicians, and policymakers. Investment in robust clinical trials, high-throughput screening methods, and bioinformatics platforms is crucial to unlocking the full potential of microalgae in 3PM. Additionally, the development of standardized regulations and quality assurance protocols will be essential for ensuring the safety, efficacy, and scalability of microalgae-derived interventions. As healthcare systems increasingly pivot toward proactive and personalized approaches, microalgae provide a sustainable and innovative avenue for addressing some of the most pressing challenges in sports medicine and beyond, positioning them as a cornerstone in the evolution of modern healthcare. Limitations of current clinical evidence and future research directions While microalgae-derived supplements, such as Spirulina and Chlorella , have demonstrated promising health benefits—including antioxidant, anti-inflammatory, and metabolic regulatory properties—the current body of clinical evidence presents several limitations that must be addressed to substantiate these claims [ 215 ]. Many RCTs investigating the effects of microalgae supplementation involve small sample sizes and short intervention periods, which may not capture long-term effects or rare adverse events [ 216 ]. For instance, studies have ranged from 8 to 12 weeks in duration, often with inconsistent results regarding outcomes like glycemic control [ 79 , 88 , 216 ]. Such constraints can lead to insufficient statistical power and may not fully represent the diverse populations that could benefit from these interventions. Additionally, heterogeneity in study designs—including variations in microalgae species, dosages, participant health statuses, and outcome measures—complicates the ability to draw definitive conclusions. For example, discrepancies in the hypoglycemic effects of algae intake have been observed, potentially due to differences in dosages and participant characteristics. These inconsistencies highlight the need for standardized protocols to facilitate more accurate comparisons across studies and enhance the reliability of meta-analyses. While the current body of evidence highlights the potential therapeutic applications of microalgae in exercise medicine, neuroprotection, and chronic disease management, it is essential to acknowledge the speculative nature of certain claims. Many of the proposed mechanisms, particularly those related to mitochondrial function, neuroinflammation, and central sensitization, are based on preclinical findings, small-scale clinical studies, or observational data. Although these studies provide valuable insights, the direct translation of such findings into clinical practice remains uncertain. The complexity of human physiology, inter-individual variability, and multifaceted disease etiologies necessitate caution when extrapolating these preliminary results to broad clinical recommendations. To establish the clinical efficacy and safety of microalgae-based interventions, rigorous, large-scale RCTs are required. While emerging studies suggest promising outcomes, they are often limited in sample size, duration, or methodological robustness, thereby restricting their generalizability. Furthermore, potential confounding factors, including dietary habits, genetic predisposition, and lifestyle variations, must be carefully controlled to ascertain the true impact of microalgae supplementation in human populations. Future RCTs should prioritize well-defined clinical endpoints, standardized dosing regimens, and biomarker-driven stratification to enhance the reproducibility and applicability of findings. Additionally, the long-term safety profile of microalgae supplementation requires further investigation. Although short-term studies indicate favorable outcomes with minimal adverse effects, the cumulative effects of prolonged intake, potential interactions with pharmacological agents, and variability in microalgae composition due to cultivation conditions warrant systematic evaluation. Without robust clinical validation, the therapeutic claims surrounding microalgae remain largely speculative, underscoring the necessity for a measured approach in integrating these bioactives into personalized medicine frameworks. By explicitly acknowledging these limitations, this manuscript aims to provide a balanced and evidence-based perspective while advocating for continued research efforts. Establishing a stronger foundation of clinical evidence through well-powered, multi-center trials will be essential for translating microalgae-based therapies into mainstream healthcare practices with confidence and scientific rigor. Moreover, the current literature exhibits mixed results regarding the efficacy of microalgae supplementation. Some studies report significant health benefits, while others find minimal or no effects. These inconsistencies may stem from differences in study design, population demographics, or the specific strains and preparations of microalgae used. Such variability underscores the necessity for more rigorous and well-designed research to determine the true therapeutic potential of microalgae. Another critical concern is the lack of long-term safety data. There is a paucity of information on the potential risks associated with prolonged high-dose usage of microalgae supplements, including the accumulation of heavy metals, interactions with medications, and other adverse effects. Comprehensive long-term studies are necessary to evaluate these risks adequately and to inform guidelines for safe daily intake. To address these limitations, future research should focus on conducting large-scale, long-term RCTs involving diverse populations to assess both the efficacy and safety of microalgae supplementation comprehensively. Standardizing study protocols—such as harmonizing variables like microalgae species, preparation methods, dosages, and outcome measures—will facilitate more accurate comparisons and enhance the reliability of findings. Exploring the underlying biological mechanisms through which microalgae exert their effects can provide insights into optimizing their therapeutic applications and identifying which populations may benefit most. Additionally, dedicated studies focusing on the potential long-term adverse effects of microalgae supplementation are essential to ensure consumer safety and to establish evidence-based recommendations for their use in health promotion and disease prevention. Emerging evidence suggests that combining microalgae-derived bioactives with neuromodulatory techniques, pharmacological anti-inflammatory strategies, and precision-based rehabilitation may enhance therapeutic efficacy in sports medicine, chronic pain management, and neurodegenerative conditions. While microalgae exhibit potent antioxidant, anti-inflammatory, and mitochondrial-supportive effects, their integration into multimodal treatment frameworks remains underexplored. Future research should investigate how these bioactives can be optimized through synergistic interactions with existing and emerging therapeutic modalities. Neuromodulation techniques, including VNS, TMS, and DBS, have shown promise in regulating neuroinflammation, central sensitization, and neuroplasticity. These modalities modulate neural circuit function and have demonstrated efficacy in conditions such as chronic pain, neurodegenerative disorders, and exercise-induced neuroinflammation. Microalgae-derived antioxidants and neuroprotective compounds, such as phycocyanin, PUFAs, and polyphenols, may enhance the effects of neuromodulation by reducing oxidative stress, stabilizing synaptic plasticity, and promoting neuronal repair. Investigating the combined application of microalgae supplementation and neuromodulatory interventions could provide a novel, non-invasive approach for optimizing neuromuscular function and pain modulation. Similarly, pharmacological anti-inflammatory strategies, such as NSAIDs, COX-2 inhibitors, cytokine-targeting biologics, and cannabinoid-based therapies, are widely used to manage exercise-induced inflammation, neuropathic pain, and neuroimmune dysregulation. However, long-term use of these drugs carries risks such as gastrointestinal complications, immune suppression, and systemic toxicity. Microalgae bioactives could serve as adjunctive agents to lower pharmacological doses while enhancing anti-inflammatory efficacy. Future research should assess whether microalgae supplementation can potentiate the effects of pharmacological interventions by modulating key inflammatory pathways (e.g., NF-κB, NLRP3 inflammasome, and TLR signaling) while reducing adverse effects. Additionally, precision-based rehabilitation strategies incorporating biomarker-driven interventions, neuromuscular stimulation, and individualized physiotherapy programs may benefit from the integration of microalgae-derived bioactives. Emerging rehabilitation techniques, such as motor imagery training, virtual reality-based neurorehabilitation, and adaptive exercise regimens, are increasingly tailored to individual inflammatory, metabolic, and neurophysiological profiles. Given the role of microalgae in mitochondrial biogenesis, muscle recovery, and cognitive resilience, future studies should explore their ability to enhance neuroplasticity and optimize rehabilitation outcomes in conditions such as musculoskeletal injuries, traumatic brain injury, and neurodegenerative diseases. To translate these synergistic approaches into personalized clinical applications, large-scale trials should incorporate multi-omics profiling (e.g., metabolomics, transcriptomics, and proteomics) to stratify patients based on inflammatory markers, oxidative stress levels, and neuromuscular adaptation potential. AI-driven modeling and real-time biomarker tracking could further refine these integrative therapeutic frameworks, ensuring that microalgae-based interventions are tailored to individual physiological responses and therapeutic needs. By advancing research on these synergistic approaches, the potential of microalgae supplementation as a key component in multi-modal interventions can be fully realized, offering a more effective, safer, and personalized strategy for enhancing human health and performance. By addressing these limitations through rigorous and well-designed research, the scientific community can better determine the true therapeutic potential of microalgae and guide evidence-based recommendations for their use in health promotion and disease prevention. Conclusions and 3PM-related outlook Microalgae, as diverse photosynthetic organisms, offer untapped potential across multiple domains, including exercise medicine, neuroprotection, and chronic disease management. With their bioactive compounds demonstrating anticancer, antimicrobial, anti-inflammatory, and immunomodulatory effects, microalgae emerge as promising candidates for advancing Predictive, Preventive, and Personalized Medicine (PPPM/3PM). This review highlights their critical role in addressing multifaceted health challenges, particularly in exercise and sports medicine, by focusing on predictive diagnostics, targeted prevention, and personalized treatment strategies. In the context of predictive diagnostics, microalgae-derived compounds, such as phycocyanin and γ-linolenic acid, show potential for identifying early biomarkers of mitochondrial dysfunction, oxidative stress, and inflammation. These biomarkers can enable the stratification of at-risk individuals, providing healthcare practitioners with critical tools for early intervention. For athletes, predictive models incorporating microalgae supplementation could anticipate susceptibility to exercise-induced damage, guiding tailored recovery protocols and optimizing performance. Targeted prevention represents another pivotal application of microalgae in the PPPM paradigm. By modulating key inflammatory and oxidative pathways, microalgae, particularly Spirulina and Chlorella , can mitigate the risks associated with neurodegeneration, exercise-induced injuries, and chronic inflammation. Their preventive potential extends to reducing oxidative stress markers such as MDA and enhancing antioxidant enzymes like SOD and GPx. Further research is needed to refine dosage regimens and identify specific microalgae strains best suited for preventing these conditions in diverse populations. Personalized treatments, a cornerstone of 3PM, can be achieved through integrating microalgae-derived supplements into individualized healthcare plans. By tailoring supplementation based on phenotypic and molecular profiles, microalgae could enhance cognitive function, regulate inflammatory markers, and improve mitochondrial health. This personalized approach could optimize both recovery and long-term health outcomes for athletes and individuals managing chronic diseases. Despite these promising applications, challenges remain in standardizing cultivation methods, ensuring product consistency, and conducting large-scale clinical trials to validate efficacy and safety. Expanding research on underexplored microalgae species, such as Tetraselmis chuii and Nannochloropsis , is essential to fully understand their mechanisms of action and broaden their applications in sports and exercise medicine. By leveraging predictive diagnostics and phenotyping, microalgae-based interventions can move beyond general supplementation to precision-targeted strategies. Future research should focus on identifying population-specific microalgae interventions, utilizing multi-omics data, and developing individualized supplementation protocols based on real-time health monitoring. This will ensure a comprehensive approach to preventive healthcare, aligning with the fundamental principles of predictive, preventive, and personalized medicine. Current clinical evidence underscores the potential of microalgae supplementation in addressing oxidative stress, inflammation, and neurodegeneration in both athletic and clinical settings. However, further high-quality trials are required to establish standardized dosages, optimal supplementation regimens, and specific microalgae strains with the most significant therapeutic potential. Incorporating validated clinical evidence will be essential for the widespread adoption of microalgae in personalized healthcare, ensuring their role in evidence-based, cost-effective strategies for disease prevention and management. By integrating microalgae into the PPPM framework, this paradigm shift from reactive to proactive healthcare can be realized, providing cost-effective, sustainable, and individualized solutions for managing physical and cognitive stressors. The inclusion of microalgae in personalized healthcare strategies offers a transformative approach to addressing global health challenges, particularly in regions with limited access to advanced medical interventions. As research and development efforts advance, microalgae will continue to shape the future of predictive, preventive, and personalized healthcare, aligning with the goals of 3PM to enhance resilience, optimize performance, and improve health outcomes across diverse populations. Acknowledgements Not applicable. Author contributions Xuanyu Bo contributed in manuscript drafting, evaluation and data collection and. Xuanyu Bo confirmed the final version for submission. Xuanyu Bo reviewed the manuscript. Funding Not applicable. Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. 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