Omega-3 LCPUFAs against Age-Related Cognitive Impairment: History
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Contributor:
Ignasi Mora
,
Lluís Arola
,
Antoni Caimari
,
Xavier Escoté
,
Francesc Puiggros

Among nutrients to cope with aging in special cognitive decline, the long-chain omega-3 polyunsaturated fatty acids (ω-3 LCPUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have emerged as very promising ones. Due to their neuroinflammatory resolving effects, an increased status of DHA and EPA in the elderly has been linked to better cognitive function and a lower risk of dementia. Recently, supplementation with structured forms of EPA and DHA, which can be derived natural forms or targeted structures, have proven enhanced bioavailability and powerful benefits. 

  • structured lipids
  • omega-3 PUFAs
  • cognitive function
  • cell senescence
  • DHA
  • EPA
  • omic technologies

1. Introduction

After the last hundred years of medical and life science technology progress and advances, people now live longer than ever before. Currently both preventive and therapeutic approaches are failing to reduce non-communicable diseases (NCDs), but they have succeeded in increasing our life-expectancy. Consequently, although human lifespan has significantly increased, our healthspan has not kept up the pace [1].
Demographically, society is getting older and the aging process includes progressive and irreversible biological changes, resulting in a growing risk of suffering from chronic diseases, cognitive impairments, physical disfunctions, and an increased probability of dying [1]. In fact, the loss of cognitive function is considered the most critical change during aging and it is projected that the patients with dementia—considered as significant loss of cognitive function which should be distinguished from neurodevelopmental disorders, such as intellectual disability [2]—will reach up to 115.4 million in 2050 [3].
The aging process is conditioned by the interactions between our genetic inheritance and environmental influences. While aging, our cells are submitted to a wide range of intrinsic and extrinsic insults, including oncogenic activation, oxidative and genotoxic stress, mitochondrial dysfunction, irradiation, and mutagenic agents [4]. In response to these disturbances, a stable state of cell cycle arrest happens and the cellular ability to proliferate decreases entering into a phase of senescence [4].
Senescent cells undergo morphology changes, chromatin remodelling, metabolic reprogramming and secrete a complex mix of mostly proinflammatory factors, like IL-1 and TNF-α. As senescent cells are more abundant, it leads to a potentially chronic inflammatory state independent from the activation of immune cells, which may impair tissue homeostasis [5]. This phenomenon of chronic low-grade systemic inflammation is called “inflammaging” and is considered to play a central role in the pace of aging, in the impairment of cognitive and physical functions and lastly, in the development of age-related disease.
In addition, many intrinsic and environmental factors generate oxidative stress which is a common phenomenon caused by an imbalance between production and detoxification of free radicals. Free radicals, mainly reactive oxygen and nitrogen species (RONS), can damage cells and tissues leading to the activation of proinflammatory pathways which contribute to the above mentioned “inflammaging” [6] leading to a higher degree of cellular senescence.
To improve the healthspan and the quality of life in the elderly, it is crucial to consider the role of preventive health interventions. Preventing disease, not only has positive health and well-being outcomes, which is the most important impact, but also wider economic significance, since the healthcare system is not prepared to handle the pressure of an aged society. Consequently, the goal of the scientific community is to find non-pharmacological therapies to prevent the most common age-related disfunctions and especially, those related with the loss of cognitive function, thus extending the well-being and optimal health of aging people for the longest possible time [7].
Following this approach, two powerful and recent strategies, functional foods and exercise, have been shown to decrease the risk of aging-related diseases. As nutrition is closely linked with health status, there is a growing demand for appropriate dietary patterns that include food supplements and functional foods to address healthy aging. Bioactive compounds with proven anti-inflammatory and antioxidant effects are suitable as anti-aging ingredients, but few of them like vitamin E, vitamin B12 and B6 or tea polyphenols have shown consistently improved cognitive effects [8][9][10][11].
Among nutrients assessed for brain health, the omega-3 polyunsaturated fatty acids (ω-3 PUFAs) must be highlighted, specifically the ω-3 LCPUFAs: DHA and EPA. Increased intake of ω-3 LCPUFAs, which are mainly found in fish and other seafood, have been associated with better cognitive function, slower rates of cognitive decline and an overall lower risk of developing dementia [12][13]. Furthermore, DHA and EPA are promising bioactive ingredients in the treatment of more severe neurological age-related disease like Alzheimer’s or Parkinson’s disease [14][15]. However, some clinical studies with healthy subjects have failed to prove a direct effect between cognitive function improvement and ω-3 LCPUFAs supplementation during aging [15].
Thanks to the research of bioactive compounds for healthy aging, new structured forms of ω-3 LCPUFAs have emerged as promising ingredients with more powerful effects than simpler forms of DHA and EPA. This group of structured PUFAs comprises a wide range of larger structures, like triglycerides, phospholipids or derived lipid mediators of ω-3 LCPUFAs, and they have been proven to have greater bioavailability and stronger anti-inflammatory and antioxidant effect than conventional ω-3 PUFAs [16][17] according to the findings from in vitro and preclinical studies.

2. Senescence, Aging and Bioactive Compounds

When the phenomenon of senescence starts to grow in the nervous system, brain function impairment occurs. To understand the relationship between senescence onset and its negative implications on the nervous system and brain function, and how nutrition can modulate this relationship, the biological mechanisms of senescence should be updated.

2.1. Nutrients and Anti-Cellular Senescence Targets

As stated above, senescence is a physiological stress response of mammalian cells that results in the development of senescent cells (SC) with distinct physical, molecular, and metabolic signatures. Based on the type of induction, three broad categories of cellular senescence are defined: replicative senescence (telomere attrition), oncogene-induced senescence (activation of oncogenes), and genotoxic or oxidative stress-induced senescence.
Regardless of the different triggers of cellular senescence, SC are invariably accompanied by impaired mitochondrial functions, increased intracellular RONS and production and activation of the DNA damage response. Late SC, exhibit characteristic secretion of a milieu of cytokines and growth factors causing a chronic inflammation state independent from the activation of immune cells which may impair tissue homeostasis, a phenomenon known as inflammaging as mentioned above [18]. As a strategy to fight against tissue homeostasis impairment, three nutrition-mediated anti-cellular senescence targets may be established, according to the current literature.

2.2. Omega-3 LCPUFAs to Cope with Senescence

Blood levels of EPA and DHA are in the low range for most of the world population [19] despite them being promising bioactive nutrients contributing to healthy aging. Both ω-3 LCPUFAs modify cellular function through overlapping and distinct mechanisms of action. An increased intake of EPA and DHA exerts an enhanced appearance of those fatty acids in the membrane phospholipids of cells [15][20].

3. Bioactive Compounds and Improvement in Cognitive Function

A progressive decline in memory, language, problem-solving and other cognitive skills that affects a person’s ability to perform everyday activities, leads to mild cognitive impairment and may progress to dementia [21].
As mentioned previously, late senescent cells and changes in microglial function (immunosenescence) cause neuroinflammation and oxidative stress due to an enhanced pro-inflammatory cytokine production and weak redox homeostasis. Inflammation and ROS drive a progressive impairment of brain cell processes, such as neural membrane fluidity reduction, less synaptic plasticity and low neurogenesis [22]. These impaired functions may lead to irreversible neural changes like loss of grey and white matter volume, and significant alterations in memory, learning abilities and spatial recognition which have been described in both humans and animals [22][23] driving the age-related cognitive decline.
Although there is much to be clarified about the specific molecular mechanisms in which dietary components influence cognitive function, a growing literature supports the idea that certain dietary patterns and some bioactive compounds are able to modulate brain structure and function, exerting their beneficial influence throughout the entire lifespan [10][24].
Vitamins of the B group have been studied for their potential effect on cognitive function because of their role in homocysteine metabolism, specially vitamins B6 (pyridoxine), B9 (folate) and B12 (cobalamin) [11]. Several clinical studies have found that raised concentrations of homocysteine in plasma might be associated with increased risk of dementia in people older than 65 years [25]. Supplementation, over 3 years, of 0.8 mg a day of folate—higher than twice the recommended daily intake [26]—improved cognition in participants aged 50–70 years, but the intervention was more effective in those with high baseline homocysteine concentrations [27]. In general, most clinical trials of B vitamins have found no association with cognitive function. Only individuals with high baseline homocysteine, low baseline vitamin B concentrations, or established cardiovascular and cerebrovascular disease may benefit most from vitamin B supplementation [10].
As the brain is highly susceptible to oxidative damage, it has been suggested that inadequate antioxidant defences might mediate the pathogenesis and progression of dementia [28]. Many antioxidant nutrients such as vitamin C, vitamin E [29], zinc [30] (cofactor for enzymes with antioxidative activity) and carotenoids [31], and non-nutrient food ingredients like polyphenols [32], anthocyanins [33], lignans [34] or allicin [35] have been proven to be beneficial for age-related cognitive impairment. But, as far as there is not a deficit of the mentioned nutrients or a pathological situation, clinical trials with supplementation of these mentioned antioxidant compounds have not demonstrated a beneficial effect on any cognitive outcome in healthy patients [10].
Despite this, among nutrients addressed for brain health, ω-3 PUFAs, specifically ω-3 LCPUFAs must be highlighted [9]. Aging is associated with decreased cerebral ω-3 LCPUFAs levels due to reduced absorption, lower ω-3 PUFA capacity to cross the blood-brain barrier [12], and decreased capacity to convert PUFAs into LCPUFAs in the brain. As a major neuronal membrane component, DHA regulates neurogenesis, synaptogenesis, and neural membrane fluidity, which in turn modulates the speed of cell signalling and neurotransmission. In comparison with DHA, EPA constitutes a minimal proportion of total brain LCPUFA, but EPA inhibits proinflammatory metabolism and promotes adequate cerebral blood flow [36]. Altogether, a large amount of evidence demonstrates that poor ω-3 LCPUFA status in brain and plasma is associated with age-related cognitive decline [37].

4. Omega-3 LCPUFAs against Age-Related Cognitive Impairment

Although DHA has a structural role as a major component neuronal membrane fatty acid, it is endogenously transformed in the nervous system to an endocannabinoid-like metabolite called N-Docosahexaenoylethanolamine (synaptamide). Mainly through the specific target receptor GPR110, a G-protein coupled receptor, synaptamide promotes neurogenesis, neurite outgrowth and synaptogenesis in developing neurons. GPR110 induces cAMP production and phosphorylation of protein kinase A (PKA) and the cAMP response element binding protein (CREB) [38]. This signalling pathway leads to the expression of neurogenic and synaptogenic genes and suppresses the expression of proinflammatory genes. GPR110 is highly expressed in the brain during development but also during adulthood, emphasizing its relevance in the hippocampal region where neurogenesis is still happening [39][40].
Once it was proven that the pharmacological inhibition of neuroinflammation improved memory in aged murine models [41], the anti-inflammatory role of ω-3 LCPUFA gained attention as a possible therapeutic nutrient for healthy aging. Recent studies with aged rats [42] and mice [22] from a preventive point of view, show an improvement in memory and cognitive skills after a reduction in microglial activation and neuroinflammation, following supplementation with EPA and/or DHA. Moreover, in animal models ω-3 LCPUFAs and SPMs also have proven neuroinflammatory resolving effects and cognition improvements in age-related diseases, like Parkinson’s [43][44].
In preclinical data, human trials show a negative correlation between increased dietary supply of ω-3 LCPUFAs and pro-inflammatory markers [45] but, a positive correlation with verbal performance and learning ability in elderly people with high risk of early cognitive decline [43]. In patients with coronary artery disease and potentially ischemic risk, which reduces cerebral blood flow and contributes to the development of dementia, a daily high-dose of 1.86 g of EPA and 1.5 g of DHA over a 30 months period enhanced cognitive function significantly in comparison with control [46]. Also in middle-aged to older adults with obesity, which accelerates cognitive decline by endothelial dysfunction (impaired vasodilatation) in the peripheral and cerebral vasculature, greater processing speed mediated by improvements in circulatory function was observed following fish-oil supplementation (total dose of 0.4 g EPA and 2 g DHA) [47]. Furthermore, a study with old adults, with no risk factors, who had self-perceived cognitive function impairment (bad memory, learning difficulty,…), reported lower levels of cognitive inefficiency in activities of everyday life following 24 weeks treatment with fish oil (daily dose of 1.6 g EPA and 0.8 g DHA) [48].
However, when the effect of ω-3 LCPUFAs are assayed in healthy older adults the results are controversial [36]. Despite reported meta-analyses highlighting the potential of ω-3 PUFA to improve memory [13] and cognitive decline [37], some interventional studies have changed the perspective of the actual benefits of ω-3 LCPUFA [49][50]. As an example, Van de Rest et al. did not find significant changes in any of the cognitive domains for either low-dose (0.4 g/day EPA-DHA) or high-dose (1.8 g/day EPA-DHA) fish oil supplementation groups compared with placebo in a cohort of healthy individuals aged 65 years or older [51]. More recently, Baleztena et al. reported that daily supplementation with 0.75 g of DHA and 0.12 g of EPA did not show an improvement in the global cognitive function in adults over 75 years of age. They just found an apparent improvement in memory loss when the study subjects were well nourished [52].
According to the literature, two main issues justify the divergences [15]. Firstly, the effect of DHA and EPA depends on the stage of cognitive health assessed. This is supported by Canhada et al. in a recent systematic review where they conclude that the most beneficial effect of EPA and DHA supplementation in Alzheimer’s patients can only be expected in the early stage of the disease [53]. Secondly, there were several weaknesses in the trial protocols designed to assess the effect of EPA and DHA, such as the variability of doses of DHA and EPA, the type of placebo used, the combination of treatments [54], the duration of treatment, the sample size, the ω-3 LCPUFA status of the participants and the cognitive outcomes/tests measured as primary and secondary variables [15].
Therefore, since clinical trials are performed with a wide range of target population and low consistency of biomarkers measured in the nutritional interventions, the results from clinical studies with ω-3 LCPUFA do not allow a consensus about how traditional forms of ω-3 LCPUFAs affect cognitive function and aging [55].

5. Structured Lipids: Innovative Omega-3 LCPUFAs Molecules for Healthy Aging

Structured lipids can be defined as chemically or enzymatically modified lipids that change the fatty acid composition and/or the positional distribution [56]. They are created to be applied in functional food and clinical nutrition because of their characteristics or bioactive properties [57][58]. These structures can be a replica of natural forms of lipids with special structures designed to have a specific function. Most of the studies mentioned above use ethyl ester (EE) forms of DHA and EPA, or oils rich in DHA and EPA-EE for supplementation. However, in natural matrixes containing DHA and EPA, like in blue fish or breastmilk, they can be found in more complex structures as phospholipids (PL) or triglycerides (TG), or in derived forms, like SPMs, synaptamide and precursors.
Studies comparing the effect of supplementation with structured TGs and PLs ω-3 LCPUFAs against EE have proven enhanced bioavailability and powerful benefits of the structured forms in comparison with EE [59][60][61]. Similar intestinal absorption capacity and bioavailability between TG and PL have been described in studies analysing the responses of blood biomarkers [62][63], however, a greater brain absorption has been observed when DHA is esterified to PL [64]. In contrast, supplemented diets with a source of PL-DHA, TG-DHA or a mixture of both, resulted in similar increases in brain DHA compared to a low ω-3 PUFA diet [65].
Positional distribution is also important in structured lipids. For example, depending on the position of the fatty acid in the glycerol backbone of the TG (three positions, sn-1, sn-2 and sn-3), higher or lower absorption of the fatty acids can be observed. After intake, hydrolysis of TGs is performed by lipases, which are typically enantioselective. In the digestive tract, fatty acids in the sn-1 and sn-3 positions of the glycerol backbone are cleaved while the fatty acids of the sn-2 position are mainly absorbed [56] as represented in Figure 1. In this sense, preclinical results show differences in bioavailability when dietary TGs had DHA in the sn-1, sn-2 or sn-3 position, explained by less secretion of fecal DHA when this was at the sn-2 position. However, the same study shows no difference in DHA content of the fasting plasma, probably because the 5-day intervention in rats was not long enough to modify the fatty acid profile of phospholipids [66].
Figure 1. A triglyceride of DHA digested by lipases. The sn-1 and sn-3 positions of the glycerol backbone are cleaved while the fatty acids of the sn-2 position remains. Image courtesy of Brudylab®.
In addition to differences in the absorption, there are also divergences in the effect on the cells despite structured ω-3 LCPUFAs share common mechanisms with EE forms as schematically represented in Figure 2. In vitro studies using DHA-TG showed powerful antioxidant responses in comparison with EE-DHA in experiments with human fibroblasts and human retinal pigment epithelium cells through enhancing GSH synthesis significantly [17]. As mentioned before, some experimental studies have provided evidence about the interrelationship between DHA and GSH mainly through the regulation of nuclear factors like NFE2L2 [67][68], however TG-DHA seems to stimulate this reported pathway stronger than EE-DHA [17][69]. Moreover, a recent clinical trial proven significant anti-inflammatory properties after supplementation with TG-DHA through reduction of proinflammatory cytokines levels in patients with recurrent uveitis, one of the major causes of vision loss [57].
Figure 2. Schematic representation of the hypothetic mechanisms through which ω-3 LCPUFAs reduce neuroinflammation and improve cognitive function by modulating inflammation and oxidative stress in brain cells. Thick arrows express the enhanced effect of the structured forms of DHA and EPA (TFs, transcription factors).
Concerning neuroinflammation and cognitive decline, in vitro and pre-clinical studies show improved efficacy when structured ω-3 LCPUFAs are used in comparison with EE [64] as detailed in Figure 2. One study where the effect of TG-DHA on microglial activation was assessed and compared with EE-DHA, proved that TG-DHA treatment protected microglia cells from oxidative stress toxicity by attenuating nitric oxide (NO) production and suppressing the induction of inflammatory cytokines [70]. Furthermore, in the same study, when 50 or 250 mg/kg of TG-DHA was given orally to mice with autoimmune encephalomyelitis for a total of 56 days, a significant amelioration of the course and severity of the disease as compared to untreated animals was observed, concluding that TG-DHA is a promising nutritional immunomodulating agent in neuroinflammatory processes [70]. Supporting this data, another study using a Parkinsonism murine model, which constitutes a powerful neurotoxic model, indicated that 250 mg/kg of TG-DHA for 22 consecutive days acted as a neuroprotective agent and may constitute a promising therapeutic adjuvant [71].
Looking for a greater bioactive and targeted effect, other types of structured ω-3 LCPUFA, in addition to PL and TG, have been tested in pre-clinical studies. This is the case with ω-3 LCPUFAs esterified with lysophosphatidyl-choline (LPC). When LPC is esterified with a saturated fatty acid it becomes a highly proinflammatory molecule, while esterification with a ω-3 PUFA, causes it to have the opposite role [72]. LPC has a great affinity for the receptor MFSD2A (sodium-dependent LPC symporter 1), a transmembrane transporter of long-chain fatty acids across the blood brain barrier (BBB) [73], located exclusively on the luminal membrane of endothelial cells that line the blood vessels in the brain [74]. Consequently, in vivo studies showed greater brain uptake of DHA and higher DHA enrichment of cell membranes in neural tissue when LPC-DHA was supplemented in comparison with PL and TG-DHA [75][76].
Another example of a special ω-3 LCPUFA is AceDoPC® [77]. It is a structured DHA-PL acetylated at the sn-1 position—structurally similar to LPC-DHA—targeted to improve brain DHA levels. In an experimental ischemic stroke rat model, the intravenous injection of AceDoPC® proved to have more powerful anti-inflammatory effects, attenuating induced neuroinflammation by decreasing IL-6 production [64], in addition to exerting more neuroprotective effects than DHA-EE in another study with a stroke rat model [78]. Moreover, a study with neural stem progenitor cells (NSPCs) derived from the adult mouse brain showed enhanced neurogenesis with AceDoPC® over DHA-EE, especially under hypoxigenic (ischemic) conditions in vitro [79].
Furthermore, supplementation with synaptamide, which is mentioned as a bioactive form of DHA in the brain, has been assayed by Tyrtyshnaia et al. using synpatamide extracted from squid and administered subcutaneously to rats as a water emulsion. Synaptamide treatment attenuated microglial activation, release of proinflammatory cytokines, and decreased hippocampal neurogenesis in rats with a sciatic nerve chronic constriction injury [80].
Studies supplementing isolated forms of SPMs, derived lipid mediators of ω-3 LCPUFA, have been performed. Although limited literature relates the anti-inflammatory effect of SPMs with cognitive decline improvement [44], successful results have been observed with the use of supplements with SPMs and precursors of SPMs. It has been proved that supplementation with an oil enriched with SPMs and precursors, significantly increases SPM concentration in peripheral blood in humans [81], and larger intervention studies have been performed demonstrating that an orally administered SPM-enriched supplement improved the quality of life and reduced pain in a sample of adults with chronic pain [82].
Considering all the favourable literature, research to test the effect on brain health of new structures of ω-3 LCPUFA must go further to gain knowledge about the promising effects of targeting the positional distribution of ω-3 LCPUFA, and to find new chemical and enzymatic modification strategies to design special structures with targeted effects.

6. High-Throughput Techniques and Biological Models to Study Omega-3 LCPUFAs and Cognitive Decline

To discover the real potential of the ω-3 LCPUFAs on healthy aging not all experimental procedures can be entirely focused on nutritional interventions. Specific mechanisms must be elucidated, and fast screening methods for new structures of ω-3 LCPUFA are needed. The following points suggest high-throughput techniques and models that provide large information in a fast and cost-effective manner that might be very helpful in the study of ω-3 LCPUFAs.

6.1. “Omic” Technologies

Thanks to innovative breakthroughs in genome sequencing, bioinformatics, and analytic tools such as liquid (LC) and gas (GC) chromatography, mass spectrometry (MS), and nuclear magnetic resonance (NMR), “omics” technologies have appeared: genomics, transcriptomics, proteomics, metabolomics, metagenomics and epigenomics [83]. They are based on high-throughput identification and quantification of small and large molecules in cells, tissues, and biofluids, and are a powerful tool for mapping global biochemical changes and discovery of biomarkers [84]. Many omics disciplines are employed in food and nutrition research, and it is a prevalent recognition among food scientist that omics-based approaches are highly effective when they are exploited properly [85].
There are different motivations for conducting omic research, but commonly, they are performed to obtain a comprehensive understanding of the biological system under study, or to associate the omics-based molecular measurements with a clinical outcome of interest [86]. Researchers now put the combination of multiple omics analyses (integrated omics) into practice to exhaustively understand the functionality of food components of which nuclear NMR and MS are major choices. Generally, NMR is easier to perform and applicable to a wider range of compounds, although it is less sensitive compared to MS-based techniques. In contrast, GC or LC are used depending on the property of the target molecules [85].
The development of omic technologies brought about the expectation that an exhaustive molecular description of aging-regulated processes should have been possible, thereby shedding light on its mechanisms [87]. They would provide fast and precise information of specific and early biomarkers of the onset of homeostatic disturbances while aging, and this could help translational clinical research to describe quantitatively or qualitatively the health status of an individual or underlying aging mechanism [88][89]. For example, mass spectrometry-based omic technologies were used to reveal metabolic changes taking place during normal brain aging: metabolomic and proteomic analyses of different regions of mouse brain during the adult lifespan demonstrated an energy metabolic drift or significant imbalance in core metabolite levels in the aged animals [90].
Furthermore, omics technologies have already been applied in studies searching for the potential metabolic pathways and integrative biomarkers that would help to understand the link between nutrition, food patterns [91][92] and brain health [93]. 

6.2. Fast and Cost-Effective Experimental Models

The place of animals in our modern societies, especially of mammals, is often debated, particularly the right to use mammals to benefit human purposes when there is the possibility that they will be harmed. Moreover, not all results obtained from animals, mainly rodents, can be directly translated to humans, although there are remarkable anatomical and physiological similarities [94]. Consequently, more researchers have started to use alternative in vivo models, such as invertebrates or fish, rather than mammals which are between in vitro and rodent models, to obtain information from a complete organism in a fast and cost-effective manner. They are especially useful for the study of regulatory pathways and cellular mechanisms, as well as being suitable as screening platforms to test drugs and bioactive compounds. In addition, since the food industry is getting more and more involved in health issues by designing innovative foods that contribute to a better nutritional profile or to a certain functionality, fast and cost-effective models can be used to pre-screen compounds with bioactivity to speed up the demonstration of active ingredient effectiveness [95]. As represented in Figure 3, the simultaneous combination of these sorts of biological models with a biology systems approach using omic technologies, will make it easier and more feasible to scale-up the business pipeline of a bioactive ingredient until scientific and legal requirements, in terms of demonstrating efficacy are met.
Figure 3. Advantages of integrating the use of omic technologies and small high-throughput in vivo models on the study of the efficacy of new structures of ω-3 LCPUFAs on cognitive function.

This entry is adapted from the peer-reviewed paper 10.3390/ijms23073472

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