What Is the Benefit of Lutein from Marigold Flower?

Lutein is a naturally occurring carotenoid that filters blue light and prevents retinal damage. Studies have shown that lutein is not only found in macular pigment, but is also widely distributed in various parts of the brain, accounting for 59% of the total carotenoids in the brain, and its concentration is positively correlated with brain development in infants and cognitive function in the elderly [1]. Preterm infants, due to their early birth, lose the opportunity to continue to obtain maternal lutein during the last few weeks of pregnancy and after birth, resulting in significantly lower lutein concentrations in the brain of preterm infants [2].

Studies have found that the lutein concentration in preterm infants is significantly lower than that in full-term infants, which may be the cause of neurodevelopmental defects in preterm infants. The increased concentration of lutein in late pregnancy is associated with the promotion of central nervous system development [3]. In contrast, low lutein levels in early infancy are associated with impaired neurodevelopment, retinal pigment epithelium maturation and an increased risk of oxidative stress in neural tissue [4]. Lutein accounts for 66% to 77% of the total carotenoids in the human brain, which indicates that lutein selectively accumulates in the brain [5], suggesting on the other hand the potential role of lutein in brain function and development. The metabolism and function of lutein in optic nerve cells and brain nerve cells are not well understood [6]. This study reviews the research progress of lutein's biological activity and function abroad to provide a scientific basis for its wider application.

1 Biological activity of lutein

Lutein belongs to the carotenoid family and can only be synthesized by plants. It is abundant in dark green leafy vegetables such as marigolds, spinach, and carrots. It is estimated that 93% of dietary lutein (lutein and zeaxanthin) is free lutein, while only 7% is esterified [7⁃8]. Comparative analysis of the bioavailability of esterified and free lutein shows that the human digestive system absorbs free lutein better and that supplementing with free lutein increases serum lutein levels more [9]. Therefore, compared with free lutein, more esterified lutein needs to be consumed to achieve the same serum lutein level.

However, there is no significant difference in plasma lutein levels in chickens after consumption of free and esterified lutein [10⁃11], which may be related to differences in enzymes metabolized in different species. Other nutrients can also promote the body's absorption of lutein. For example, when used in combination with phospholipids, lutein absorption levels can be increased. In a study comparing the absorption efficiency of lutein phospholipid and lutein ester, it was found that after taking lutein capsules containing phospholipids for 10 days, adult plasma lutein levels were significantly increased (about 6 times higher) [12]. This result also explains the high availability of lutein in egg yolk, where lutein may be esterified with phospholipids. However, there is currently no comparison of the biological activity of phospholipidized lutein and free lutein.

Differences in lutein intake may be the reason for the different lutein levels in the body. Lutein is the most abundant carotenoid in breast milk, and the bioavailability of lutein in breast milk is higher than that in infant formula [13]. This difference may be due to factors such as the quality of the mother's food, fat intake, and the interaction between nutrients, which indirectly affect the nutrient composition of breast milk [14⁃16].

The bioavailability of lutein is also related to the method of supplementation. A study of the availability of lutein in breast milk and formula feeding in rhesus monkeys (primate mammals) showed that at 6 months of age, compared to the formula group without lutein, the lutein concentration in the blood and all tissues of the formula-fed monkeys supplemented with lutein increased, with the highest concentration in the occipital cortex; however, the lutein concentration in the blood, all brain tissues, the macula and retina, adipose tissue, liver, and other tissues of the breast-fed monkeys was higher than that in the lutein-supplemented formula group, indicating that the bioavailability of lutein in breast milk is the highest [17]. The bioavailability of lutein may also be affected by the level of lutein transport protein in the blood plasma – high-density lipoprotein (HDL). Connor et al. [18] found that feeding chickens deficient in HDL apolipoprotein with a high lutein diet resulted in almost no change in lutein levels in the blood plasma and retina, while lutein levels in the control group of chickens increased significantly. Further studies on the transport of lutein in the blood of patients with age-related macular degeneration and normal people found that 52% of the lutein in the blood plasma is transported by HDL and 22% by LDL, and that the transport of carotenoids by HDL and LDL is independent of the presence or absence of macular degeneration.

2 Lutein metabolism in the body

After being transported to the target area by carriers such as HDL, lutein binds to the acute regulatory domain protein StARD3 produced by retinoids and then enters the cell to exert its function [19⁃21]. In addition, as a member of the carotenoid family, lutein can also be metabolized and broken down by β-carotene oxygenase (BCO). BCO can cleave carotenoids by symmetric and asymmetric decomposition to produce retinal, which can further catalyze the production of the well-known differentiation inducer RA. Among them, BCO1 performs symmetric cleavage at the middle position of the carotenoid, while BCO2 performs the asymmetric cleavage. BCO1 can metabolize β-carotene to produce retinal at a rate of 197 nmol/mg BCO1/h, but the rate of BCO1 cleaving lutein is zero [22]. BCO2 is mainly responsible for the metabolism of lutein. Surface affinity analysis has found that the affinity of BCO2 for lutein in humans and mice is very high, while the affinity of BCO2 for lutein in the human eye is 10 times lower [23]. This is the reason why lutein can accumulate in the human eye to form the macula without being broken down by BCO2. In fact, knocking out the BCO2 gene in mice can significantly increase the concentration of lutein in the retinal pigment epithelium, further confirming that BCO2 is a metabolic enzyme for lutein [24].

Lutein is a type of vitamin A. Low concentrations of vitamin A and its metabolites can lead to failed nerve extension, apoptosis of nerve cells and developmental defects in the central nervous system [25]. Olson et al. [26] showed that retinoic acid (RA), the main metabolite of vitamin A, can react with many cell surface receptors (retinoic acid and retinoic acid receptors) that regulate gene transcription and cell signaling and play various roles in the differentiation and maintenance of neuronal phenotypes. Retinoic acid induces cell differentiation and tissue development and is considered to be crucial for early neurogenesis [27]. At the cellular level, RA may induce cell differentiation by regulating the cell cycle of undifferentiated precursor cells [28]. RA-induced neuronal differentiation of SY5Y neuroblastoma cells is associated with its regulation of cellular metabolic functions [29]. This “metabolic remodelling” may even be a crucial factor in the physiological dialogue that supports the differentiation process, reflecting the different bioenergetic requirements of mature cells and the bioavailability of intracellular metabolic intermediates, which are essential for the regulation of gene expression [30].

3 Lutein's antioxidant effect

Reactive oxygen species (ROS) in the body include a series of oxidized compounds that have not been completely reduced [31], and they are usually by-products of metabolic reactions in the body. Lutein's good antioxidant effect is mainly achieved by reducing the expression of inflammatory factors and increasing superoxide dismutase. Mariko et al. [32] used a mouse model of endotoxin-induced uveitis in the eyes to study the effect of lutein. lutein can alleviate the concentration of oxidative active substances in the mouse's eyes, reduce the expression of inflammatory factors, and protect against pathological changes in Muller glial cells, suggesting that lutein can protect optic nerve cells from inflammation in the uvea through its antioxidant effect.

In another experiment using 3 h of 2,000 lux blue light to damage the retinal degeneration of mice, Mamoru et al. [33] found that Lutein-treated mice reduced ROS concentrations by increasing the mRNA expression of superoxide dismutase SOD1 and SOD2 and increasing their enzymatic activity. Lutein also reduced the expression of macrophage markers, suggesting that it reduced the inflammatory response after blue light damage and helped repair the visual damage caused by blue light. Lutein not only reduces ROS concentrations in optic nerve cells, but also has a good antioxidant effect on other tissues.

Shi Yu Du et al. [34] found in a mouse model of alcoholic liver injury that after lutein pretreatment, the ROS in the mouse liver was significantly reduced and the activity of antioxidant enzymes was significantly increased, indicating that lutein can reduce alcoholic liver cell damage by increasing antioxidant capacity. In a mouse model of ischemia-reperfusion injury, lutein treatment also significantly reduced oxidative stress in skeletal tissues, protein carbonylation and sulfhydryl groups, and lipid peroxidation [35]. Lutein also plays an important role in protecting brain tissue. It has been found that in mice with severe traumatic brain injury, the expression of inflammatory factors IL-1β and IL-6, and the concentration of ROS in the serum, were significantly reduced after lutein pretreatment, indicating that lutein can effectively protect against severe traumatic brain injury by reducing inflammatory and oxidative reactions [36].

4 Lutein's protective effect on brain function

There has been little research on the role of lutein in nervous system development. In addition to its antioxidant effect, lutein is preferentially absorbed by brain tissue, there has recently been increasing interest in the effect of lutein on brain tissue development [37]. Vishwanathan et al. [38] found that although lutein only accounts for 12% of the total carotenoids in the diet, it accounts for 59% of the total carotenoids in the brain and is the most abundant carotenoid in the infant brain. Analysis of lutein and its metabolites in infant head tissue revealed that lutein concentrations in brain tissue related to learning and memory (cortex, hippocampus and occipital lobe) are closely related to lipid metabolism, amino acid neurotransmitters and carnosine metabolism. Compared to full-term infants, the brain lutein concentration of premature infants is significantly lower, indicating that the late stage of pregnancy is a critical period for infants to obtain lutein from the mother, which corresponds to a critical period for infant brain development [2, 39].

Based on the concept that optimal brain development requires an optimal nutrient combination through a variety of foods, an electrophysiological study (by measuring the electrical wave response) was conducted on 6-month-old infants to test the relationship between nutrients in breast milk and recognition memory (a neurocognitive indicator) in infants who received breast milk. The study showed that infants fed breast milk with a higher lutein and choline content had better neurocognitive abilities, so that a specific combination of these nutrients may be important for the development of recognition memory [40].

In addition to helping infants and young children develop their nervous systems, lutein may have a direct effect on the differentiation of human stem cells [41]. It has also been reported that lutein's neurodevelopmental effects are related to its antioxidant effect on docosahexaenoic acid (DHA), which maintains DHA's biological activity by protecting it from reduction [42], enhances brain function by strengthening gap junctions between neurons [43], or lutein affects fatty acids and neurotransmitters in the infant brain, promoting cell membrane maturation and cortical folding [3]. In addition, lutein's anti-inflammatory and antioxidant effects may also prevent the occurrence of neurodevelopmental disorders associated with ROS, thereby protecting the healthy growth of newborns, especially premature infants [3].

In the elderly, although lutein concentrations are lower than in infants, lutein also has a positive effect on cognitive function [44]. Lutein may slow or prevent cognitive decline by preventing brain aging. Older adults with higher serum lutein levels have thicker gray matter in the parietal region of the hippocampus and perform better on crystallized intelligence tests [45]. Additional lutein supplementation not only improves the cognitive performance of the elderly, but also prevents the occurrence of related diseases: supplementing elderly women with mild cognitive impairment and low lutein concentrations in the body can significantly improve their verbal fluency [37]; in another 5-year study, supplementation with lutein in the elderly was found to reduce the risk of age-related macular degeneration by 25% [46].

5 Potential mechanisms by which lutein affects brain function

During the development of the nervous system in infants and young children, a large number of neural stem cells need to differentiate and mature into neurons. This differentiation process is accompanied by significant changes in gene and protein expression, as well as the nervous system's huge demand for neurotransmitters and energy metabolism, which generates oxidative stress. Lutein may play an important role in this process.

5.1 Metabolic reprogramming is the basis for the differentiation of brain nerve cells

In undifferentiated nerve cells, most of the energy is produced by glycolysis, which is consistent with the rapid biological energy and relatively low material synthesis required during the cell proliferation cycle [47]. The glycolytic metabolism of neural stem cells is beneficial for the use of extracellular nutrients and glucose to produce ATP and intermediates required for biosynthetic pathways, including ribose, glycerol and citric acid [48]. Another benefit of anaerobic glycolysis is that it produces less peroxide under hypoxic conditions, thereby better protecting cell DNA from mutations and damage [49].

Therefore, culturing mesenchymal stem cells and neural stem cells (NSCs) under hypoxic conditions is an important condition for maintaining the stem cells' “pluripotency” [50]. In contrast, differentiated mature nerve cells require more ATP energy to maintain and restore ion gradient conservation, produce neurotransmitters, and meet the needs of normal cell function [51⁃52]. Therefore, the metabolic “shift” from inefficient glycolysis to efficient mitochondrial oxidative phosphorylation is a key step in meeting the increased energy requirements of the mature brain [30, 53]. In contrast, when somatic cells are induced to become pluripotent stem cells, the dedifferentiation of somatic cells into stem cells requires a decrease in aerobic metabolism and an increase in glycolytic flux [54].

5. 2  Cellular metabolic state regulates cell differentiation through epigenetics

Epigenetics refers to the regulation of gene expression without altering the DNA sequence, usually through changes in histone deacetylation (HDAC), DNA methylation or similar modifications, which mediate the binding of repressor complexes to silent regulatory regions of DNA. Most enzymes that regulate chromatin conformation require cellular metabolic intermediates as substrates or cofactors, suggesting that cellular metabolism plays a key role in regulating epigenetic modifications [55].

When the cell has sufficient energy, the chromatin is acetylated and the helix is unwound, allowing the gene to be transcribed into mRNA [56]. Mitochondria can also affect gene expression by influencing the concentration of key epigenetic cofactors at the metabolic level, including ATP, acetyl coenzyme A, NADH/NAD+ and S-adenosylmethionine (SAM) [57]. When mitochondrial function is disrupted, it can disrupt the activity of DNMT and the methylation process. The loss of mitochondrial DNA can significantly change the methylation pattern of many genes, and these changes are rapidly reversed after mitochondrial DNA re-enters the cell [58].

The glycolytic process breaks down glucose to produce pyruvate, a process accompanied by the conversion of NAD+ to NADH, inhibits the deacetylase activity of SIRT1 histone; pyruvate can be further dehydrogenated to acetyl coenzyme A, which promotes histone acetylation; acetyl coenzyme A also promotes the TCA cycle and mitochondrial respiration, and the ATP produced can be used to form the methylation substrate SAM. These epigenetic rules regulate the expression of neuronal genes during differentiation.

5. 3 Lutein's role in regulating neural differentiation during cell metabolism

Regulation of cell metabolism may be the way in which lutein exerts its biological effects. Xie et al. [59] found that lutein treatment can significantly increase mitochondrial metabolism, change the epigenetic state of the cell, and promote the differentiation of undifferentiated neural cells into mature neural cells. Polyphenolic compounds can increase the rate of glycolysis and oxidative phosphorylation during the differentiation of various cell types, including adipocytes [60], muscle cells [61], and neurons derived from RA-induced SY5Y cells [29].

Polyunsaturated fatty acid DHA and dietary carotenoids have also been found to induce metabolic reprogramming during the differentiation of SY5Y neuronal cells [59], increasing glucose consumption, glycolytic rate and enhancing mitochondrial complex I/III respiration. PI3K-dependent metabolic regulation is associated with the transition of rapidly proliferating precursor cells to post-mitotic differentiated neuronal cells and may be a key pathway by which retinoids regulate neurodevelopment. PI3K/AKT inhibitors can inhibit RA[28 ,62] and lutein-induced neuronal differentiation. RA induction leads to elevated levels of the cell cycle-dependent kinase inhibitors p21 and p27 (Kip) proteins, which inhibit cell proliferation by blocking G1/S phase cell cycle progression[28]. Similarly, lutein also inhibits SY5Y proliferation, thereby enhancing neuronal differentiation [59].

The carbon metabolic pathway is coupled to mitochondrial respiratory chain activity, which affects the electrochemical potential difference between mitochondrial NADH and cytosolic NADPH, which in turn regulates the serine catabolism/anabolism cycle [63]. Therefore, changes in mitochondrial function can regulate carbon metabolism and thus alter gene expression [64]. Micronutrients such as lutein, folate, vitamin B12 and PUFAs are major influencers of carbon metabolism, thereby controlling the levels of key signalling molecules such as ATP, acetyl coenzyme A, NAD+/NADH, SAM and other TCA intermediates, which provide methyl groups for many methyltransferase reactions [65].

Animal studies have found that the nutritional status of the mother during pregnancy has a significant impact on the gene expression of epigenetic regulation in infants [66⁃67]. The production of s-adenosylmethionine (SAM), the main cellular methyl donor (affecting DNA methylation), depends on the mitochondrial folate cycle and ATP synthesis [63, 68]. SAH is a potent inhibitor of the DNA demethylase and can be hydrolyzed to homocysteine for methionine regeneration, a process that also depends on carbon metabolism [69]. Other mitochondrial metabolites such as succinate, fumarate and 2-hydroxyglutarate and α-ketoglutarate (αKG) can regulate DNA methylation via TETs [55, 70], promote TET-mediated demethylation by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) [71]. Genomic histone modifications are also affected by retinoid substances. In rats deficient in vitamin A, the RARα and CREB-binding protein-mediated acetylation of histones is significantly lower, inhibiting the expression of these genes and thus impairing the rat's learning and memory abilities [72].

In contrast, RA treatment reduces the levels of deacetylases and increases the levels of H3K27ac on the Hoxa1, Cyp26a1, and RARβ2 genes in embryonic stem cells, thereby positively affecting the expression of these genes [73]. In embryonic stem cells, HDACs bind differentially to the promoters and enhancers of genes regulated by RA. RA induces the removal of HDACs in a regulated manner and promotes the deposition of the H3K27ac mark on these genes [73]. In addition, the acetyl substrate acetyl-coenzyme A can also be produced by the oxidative degradation of certain amino acids (rather than by the oxidation of pyruvate during glycolysis). Its production process is highly dependent on the oxidation of long-chain fatty acids, and fatty acid-derived carbon can even account for up to 90% of the acetylation of certain histone lysine residues [74].

6 Conclusion and outlook

Lutein not only passes through the blood-brain barrier, but may also have a special effect on maintaining brain function. It is not only beneficial for maintaining cognitive and language abilities in the elderly, but may also be involved in the development of the brain's nervous system in infants and young children. The possible mechanism of its brain health function is that lutein can regulate cell metabolism, promote the shift from glycolysis to oxidative phosphorylation, thereby changing the epigenetic state of cells/tissues and regulating gene expression related to neuronal cell differentiation/development. China has long been among the world leaders in terms of the number of newborns, and with the advent of an aging society, there is a huge demand for brain function protection in infants and the elderly. Lutein has great potential for application in the field of brain function protection.

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