Algae as Functional Foods for the Elderly

Filipa Figueiredo¹, Telma Encarnação², Maria G. Campos^1,2

¹Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, Coimbra, Portugal.
²Chemistry Centre of Coimbra, Faculty of Science and Technology, University of Coimbra, Coimbra, Portugal.

DOI: 10.4236/fns.2016.712107                

Abstract

Older people may have more difficulties in acquiring the nutrients they need from diet and they are at greater risk of chronic diseases. Hence, functional foods based on algae, might have a role in improving very important nutrients intake without an increase in calories. This is crucial for middle age people that become less active and will not dispend as much energy as they use to, which will contribute for certain diseases associated with age. Algae produce a great variety of biological active compounds which cannot be found in other organisms. Moreover, they have been reported for their potential medicinal uses. Therefore, they have high potential as a source of functional ingredients. In this review, we will give relevant information about the issue, explain above, pointing out the information related to the compounds that could be responsible for the improvement in quality of life during elderly. It will be also referred that seaweeds can be a source of new compounds for drug discovery.

Keywords

Functional Foods, Algae, Elderly, Antioxidant, Inflammation, Diabetes, Obesity, Neuroprotection

1. Introduction

Diet plays a primary role of providing enough nutrients to meet metabolic require- ments. However, diet may also modulate various functions in the body, thus playing detrimental or beneficial roles in some diseases [1] . There are scientific papers that correlate diet and some chronic diseases, showing the extraordinary possibility of foods to support, or even improve, our health [2] [3] . Based on this hypothesis, food may not only be used to survive and provide hunger satisfaction, but also to promote the state of well-being and better health and to help to reduce the risk of diseases. This might be particularly important given the increasing cost of health care, the steady increase in life expectancy and the desire of older people for improved quality of life [1] .

Food that, besides its nutritious effect, has a demonstrated benefit for one or more functions of the human organism, improving the state of health or well-being or re- ducing the risk of disease, can be considered “functional” [4] . Besides, it has also to have effectiveness at normal consumed doses [5] . The action of functional foods is due to a component or series of ingredients [5] , may or may not be nutrients [1] , that are not present in the analogous conventional food or are present at lower concentrations. These are called functional ingredients [5] .

Older people may have more difficulties in obtaining the nutrients they need from diet, because of age related changes. Moreover, there is an increase in the risk of chronic disease with age, which can mean that older people may need more radical dietary changes to prevent or manage chronic conditions [6] . Hence, functional foods can have a role in improving nutrient intake [7] and in reducing the risk of chronic diseases associated with age [6] .

Algae are photosynthetic organisms, with great diversity of forms and sizes, that range from unicellular microscopic organisms (microalgae) to multicellular of great size (macroalgae) [5] . Marine macroalgae, also referred as seaweeds, can be classified into three groups, based on their pigmentation, brown (Phaeophyceae), red (Rhodo- phyceae) and green (Chlorophyceae) algae [8] . They are, among marine organisms, a rich source of structurally diverse bioactive compounds with various biological activi- ties and their importance as a source of novel bioactive substances is growing [9] - [11] .

Some algae live in complex habitats and are submitted to extreme conditions such as changes in salinity, temperature, nutrients, UV-VIS irradiation and others. In order to survive, they must adapt rapidly to the new environmental conditions, producing a great variety of secondary metabolites which cannot be found in other organisms [12] . Many metabolites isolated from marine algae have already been reported for their bio- logical activities and potential health benefits [13] . Current research has revealed that seaweeds have potential medicinal uses against cancer, allergy, diabetes, oxidative stress, inflammation, thrombosis, obesity, lipidemia, hypertensive and other degenera- tive ailments [14] . Moreover, due to their great taxonomic diversity, the search of new biological active compounds from algae can be seen as an almost unlimited field [5] and marine algae are still identified as an under exploited plant resource [15] .

Other important aspects are the fact that algae are easily cultivated, with rapid grow- ing (for many of the species) and the possibility of controlling the production of some bioactive compounds by manipulating the cultivation conditions. Hence, algae and mi- croalgae can be considered natural reactors and a good alternative to chemical synthesis for certain compounds [5] .

2. Main Compounds

All algae primarily contain proteins, carbohydrates, fats and nucleic acids in varying proportions. Many are cultivated for their nutritional value as they are particularly nutritious and able to provide many vitamins such as A, B1, B2, B6, niacin and C [16] . Edible seaweeds are also rich in bioactive antioxidants, soluble dietary fibres, minerals, phytochemicals and polyunsaturated fatty acids, with low caloric value. However, nu- trient contents are affected by external aspects such as geographic location, environ- mental conditions and season [14] . Besides their nutritional value as supplements and food source [16] seaweeds have revealed to possess numerous beneficial health effects [17] . They have been shown to have therapeutic properties for health and disease man- agement, such as antioxidant, antitumor, anti-inflammatory, anti-obesity, neuroprotec- tive, among other properties [14] . These activities are due to active compounds includ- ing sulphated polysaccharides (SP), phlorotannins, peptides [14] and natural pigments (NP) [13] .

Marine algae represent the most important non-animal source of sulphated polysac- charides. These compounds are anionic polymers which structure varies according to the algal species [18] . Their biological activities depend on chemical structure, molecular weight and chain conformation [19] . The most abundant SP found in marine algae are fucoidan and laminarans of brown algae, carrageenan of red algae and ulvan of green algae [20] [21] . Fucoidans have been reported by their antioxidant, anti-inflammatory, anti-allergic, anti-tumour, anti-obesity, anti-coagulant, anti-viral, anti-hepatopathy, anti-uropathy and anti-renalpathy effects. Plus, they are widely available commercially from various cheap sources when compared to other SP. Hence, they have been more and more investigated to develop functional foods [22] , for disease prevention and health promotion [23] . Fucoindans from seaweeds are heterogenic compounds, being a mixture of structurally related polysaccharides with certain variations of the content of carbohydrate units and non-carbohydrate substituents [24] . They are essentially com- posed of fucose and sulphate, and also contain other monosaccharides like mannose, galactose, glucose, xylose, etc., and uronic acids [23] .

Another interesting feature of marine algae is their richness in NP [13] which can be classified into chlorophylls, carotenoids and phycobiliproteins. Chlorophylls are greenish lipid-soluble NP with a porphyrin ring [25] . The most important one is chlorophyll a, [26] but there is also chlorophyll b, c, and d [27] . Carotenoids have an important func- tion, in algae, of inactivating reactive oxygen species (ROS). They are linear polyenes [28] that can be classified into carotenes (unsatured hydrocarbons) and xanthophylls (where one or more functional groups contain oxygen) [29] . Among carotenoids, fucoxanthin is a very visible one [30] , with an unusual allenic bond and a 5,6-monoepoxide [31] . Phycobiliproteins are water soluble fluorescent proteins [29] that can be divided into phycocyanins, allophycocyanins and phycoerythtins [32] [33] .

Marine brown algae contain a variety of phloroglucinol-based polyphenols as phlorotannins. These compounds consist of phloroglucinol (1,3,5-trihydroxybenzene) monomer units, linked to each other in various ways [34] . According to the means of linkage, phlorotannins can be classified into fuhalols and phlorethols (ether linkage), fucols (phenyl linkage) fucophloroethols (ether and phenyl linkage) and eckols (diben- zodioxin linkage) [35] .

3. Bioactivities

3.1. Antioxidant Properties

The use of oxygen, in normal metabolism, leads to the production of reactive oxygen species (ROS) [36] , which can react with molecules in living cells such as lipids, sugars, amino acids and nucleotides [37] . The endogenous antioxidants such as superoxide dismutase, catalase and glutathione peroxidase and non-enzymatic antioxidants such as vitamine C, α-tocopherol and selenium are very important. They reduce these oxidant reactions [38] that can be highly toxic and deleterious to cells and tissues [36] . The im- balance between antioxidants and oxidants, in favour to oxidants, results in health is- sues such as cancer, neurodegenerative disease, autoimmune conditions [39] - [41] , car- diovascular disease, hypertension, diabetes mellitus, inflammatory disease and aging [42] . There is an interest in the food and pharmaceutical industry for the development of antioxidants from natural sources as safe alternatives of synthetic commercial anti- oxidants [23] .

It has also been proposed that oxidative damage determines life span. However, even though multiple studies support the association between age-related disorders and oxi- dative damage, the data does not support or remains inconclusive, whether it deter- mines life span [43] .

Moreover, the balance between oxidants and antioxidants is an important determi- nant of immune cell function. Optimal amounts of antioxidants are needed for main- tenance of immune response, particularly in aged people as age-associated dysregulation of immune response is well documented. There is an age-related increase in free radical formation and lipid peroxidation, which contributes, in part, to this phenomenon [44] .

Generally, the consumption of seaweed increases the activity of superoxide dismutase, glutathione peroxidise and sometimes catalase, which are endogenous antioxidant enzymes [45] - [47] .

Sulphated polysaccharides from algae have potential antioxidant activity. Fucoidan, laminaran and alginic acid in particularly, have been shown as potent antioxidants [48] - [50] . It has been reported in vivo antioxidant activity of SP from Porphyra haita- nensis in aging mice [51] . Fucoidan from Fucus vesiculosus prevented the formation of superoxide radicals, hydroxyl radicals and lipid peroxidation [52] . The ones from Laminaria japonica have shown to possess scavenging capacities on superoxide radical and hypochlorous acid (HOCl) [53] and protective effect on LDL oxidation induced by the radicals AAPH and AMNV [54] . Hipochlorous acid is a powerful oxidant. It con- tributes to the microbial killing which leads to the injury of host tissue and triggers severe inflammation disorders [55] . Moreover, in an in vivo experiment on diabetic mice, fucoidans from this specie prevented the increase of lipid peroxidation in serum, liver and spleen [56] . These results on fucoidans indicate their potential for preventing the free radical-mediated diseases [23] .

Marine brown algae also accumulate phloroglucinol-based polyphenols as phloro- tannins [35] . These compounds have strong antioxidant activities against free radical mediated oxidation damage. This activity can be due to the scavenging of radicals formed during peroxidation, the scavenging of oxygen-containing compounds or to the metal-chelating activity [35] . Ecklonia cava’s phlorotannins were isolated for the evalu- ation of their antioxidant properties. The results show that most of the tested phloro- tannins derivatives have significant total antioxidant activity in comparison to toco- pherol. They also presented potential against DPPH, hydroxyl, superoxide and peroxyl radicals when their scavenging activity was tested. The cellular ROS inhibition assay and the membrane protein oxidation assay confirmed these results. Based on this study the authors claim that the phlorotannins from E. cava “have noteworthy potential for application as antioxidants in functional foods” [55] .

Furthermore, phlorotannins from Ecklonia kurome, Ecklonia bicyclis and Hizikia fusiformes also revealed potent antioxidant activity and protective effect against hy- drogen peroxidase-induced cell damage [57] - [59] .

As described above, natural pigments, including fucoxanthin, phycoerithrobilin, chlorophyll a and their derivatives, present antioxidant activities [13] . Chlorophyll a reacts with peroxyl radicals leading to inactive products [60] [61] . Its derivatives have shown more potent antioxidant activity [60] and chlorophyll b derivatives even more [62] . Fucoxanthin is a carotenoid which colors brown algae and diatoms [13] . Its oral administration to broiler chicks improved plasma antioxidant status [63] . Moreover, it was reported that fucoxanthin has cytoprotective effect against ROS formation induced by H₂O₂ in vitro [64] .

Finally, some research works have focused on antioxidant properties of protein hy- drolysates and peptides. Antioxidative effects of water-soluble, protease enzymatic ex- tracts of marine edible brown seaweeds were reported. This included Ecklonia cava, Scytosiphon lomentaria, Ishige okamurae, Sargassum fullvelum, Sargasum horneri and Sargassum thunbergii. The enzymatic extracts of E. cava were the ones to scavenge DPPH free radicals more effectively. The highest inhibitory capacity of lipid peroxida- tion in linoleic acid was observed in alcalase extract of E. cava and neutrase extract of S. lomentaria [65] . In another study, S. lomentaria showed strong ROS scavenging activities after being hydrolysed by proteases [66] . In addition, enzyme assisted extractions (EAEs) from Palmaria palmate, a red algae, exhibited the greatest scavenging activities against DPPH and peroxyl radicals when treated with proteases than carbohydrases [67] . EAEs of Undaria pinnatifida, have also exhibited strong scavenging activities against DPPH and hydroxyl radicals, when treated with proteases [68] . Several studies have confirmed that low molecular weight hydrolysates have more potency to possess ROS scavenging activities than the high weight ones [69] . Pepsin hydrolysate from Chorella vulgaris protein waste showed potent antioxidant activity. The purified peptide from algal protein has shown highersuperoxide radical scavenging activities when compared to standard antioxidants. Furthermore, moderate antioxidative and scavenging effects were reported against DPPH radicals [70] . Hence, antioxidative protein hydrolysates, peptides or amino acids from marine algae may be potential sources to control various oxidative processes. However, due to the diversities of in vitro assay systems and inconsistency in the conditions used to evaluate their antioxidative capacity, it is difficult to compare the results from different studies [71] .

3.2. Anticancer Activity

The likelihood of developing cancer increases with age, for both men and women, with only a small proportion known to be inherited [72] (WCRF, 1997).

Seaweeds regular intake was associated with lower risk of: rectal cancer [73] as well as benign and neoplasis cancer risk [74] [75] ; and human breast cancers [76] with sup- pressive effects on the development of benign and cancer neoplasis [77] .

Free radicals induce the formation of cancer cells in human body and so, oxidative damage is an important contributor in carcinogenesis. Hence, compounds with radical scavenging activity, such as the NP [13] , SP [17] and phlorotannins [35] can be used indirectly to reduce cancer formation [13] .

Phlorotannins derivatives from E. cava, such as fucodiphloroethol G, dieckol, ekol and phlorofucofurofuroeckol, demonstrated cytotoxic effect on human cancer cell lines including HT1080 (fibrosarcoma cell line), AS49 (lung cancer cell line) and HT-29 (human colon adenocarcinoma grade II). However, they were less cytotoxic to human normal lung fibroblasts [78] . Dioxinodehydroeckol, another phlorotannin derivative also from E. cava, reduced the growth of human breast cancer cells (MCF-7) by induc- tion of apoptosis [79] .

Regarding NPs, chlorophyll and its derivatives presented in vitro antimutagenic effect against numerous dietary and environmental mutagens [80] . Lutein, β-carotene and chlorophyll a from Porphyra exhibited anti-mutagenic activity in bacterial Salmo- nella typhimurium [81] . Other NPs studied for their anticancer qualities were the caro- tenoids. Adult T-cell leukaemia is an incurable and fatal malignancy of T lymphocytes caused by human T-cell leukaemia virus type 1 infection [13] . Fucoxanthin presented anti-adult T-cell leukemic effects [82] as it induced apoptosis on human leukaemia cells (HL-60) [83] [84] . Moreover, fucoxanthin demonstrated anti-proliferative effects and induced apoptosis in human colon cancer cells (caco-2, HT-29 and DLD-1) [85] and induced apoptosis in human prostate cancer cells [86] [87] (PC-3, DU145 and LNCaP). Exposure to this compound also decreases the level of apoptosis suppressing protein (Bcl-2) [86] .

Angiogenesis is the process of new blood vessels formation from a pre-existing vasculature [88] . This can either occur under physiological or pathological conditions such as inflammatory diseases, rheumatoid arthritis and tumour metastasis where the chronic unregulated angiogenic state can help spreading of the diseases [89] . Hence, preventing angiogenesis is a promising approach in the prevention of angiogenic-related diseases [13] such as cancer, where the active supply of blood to tumour tissue is reduced [90] [91] . Fucoxanthin suppressed the differentiation of endothelial progenitor cells, of the umbilical vein, into endothelial cells involving new blood vessels formation [92] . In an in vivo and ex vivo angiogenesis assay, using a rat aortic ring, fucoxanthin and fucoxan- thinol suppressed microvessel outgrowth [92] . Siphonaxanthin, from the algae Codium fragile, also possess anti-angiogenic effect, comparable with fucoxanthin [93] .

SPs are also radical scavenging compounds but their anticancer activity goes beyond that [17] . They have demonstrated antiproliferative activity in cancer cell lines in vitro and inhibitory activity of tumour growth in mice [19] [48] and anti-metastatic activity [94] . This last activity is achieved by blocking the interaction between cancer cells and basement membranes [19] [94] . However, the exact mechanism of action by which tu- mour cell proliferation and tumour cell adhesion to various substrates are inhibit is not yet completely understood [17] . Porphyrans, the SPs from Porphyra, induced in vitro apoptosis in AGS human gastric cancer cells, in a dose-dependent manner, without af- fecting the growth of normal cells [95] .

Fucoidans present anti-tumour activity due to their ability to inhibit the proliferation of tumour cells; stimulate the apoptosis of tumour cells; block tumour cells metastasis; enhance immune responses 23 and their anti-angiogenic effect [90] [91] . The anti-pro- liferative activity was observed with Cladosiphon okamuranus’ fucoidans, in human leukemic monocyte lymphoma cell line (U 937). This was caused by inducing apoptosis via caspase-3 and 7 activation dependent pathways [96] . The growth of peripheral blood mononuclear cells of adult T-cell leukaemia patients and human T-cell leukaemia virus (HTLV) type 1-infected T-cell lines was also inhibited. However, the normal pe- ripheral blood mononuclear cells were not. The apoptosis of HTLV-1-infected T-cell lines was achieved by down regulation of cellular inhibitor of apoptosis protein 2 [97] . Moreover, MDA-MB-231 breast carcinoma cell adhesion to platelets was blocked by fucoidans from L. saccharina, L. digitata, Fucus serratus, Fucus distichus and Fucua vesiculosus. This might have critical implications in tumour metastasis [23] . Anti- metastatic activity was also observed with fucoidan from Fucus evanescens, when 10 mg/Kg of it was administrated to C57Bl/6 mice with Lewis lung adenocarcinoma [98] . A variety of sulphated polysaccharides, such as fucoidans and heparin, reduced lung metastasis resulting from the intravenous injection of cells from the rat mammary adenocarcinoma 13762 MTA [99] . Finally, fucoidan increases the quantity of macro- phages [100] ; mediates the destruction of the tumour through type 1 T-helper (Th1) cells and NK response [101] and activates lymphocytes and macrophages mediated by production of free radicals (nitric oxide and H₂O₂) and cytokines-tumour necrosis fac- tor α (TNF-α) and interleukin-6(IL-6) [102] . This enhancement of immune responses inhibits tumour growth and metastatic process [100] .

3.3. Effects on Inflammation and Immunomodulating Activity

The immune system reduces its responsiveness with age, in a process known as immunosenescence [103] . The dysregulation of the immune response makes older people less capable of fighting disease [103] - [105] , reduces the effectiveness of vaccination [103] [104] and predisposes them to higher incidences of infectious, autoimmune and in- flammatory diseases [106] .

Inflammation is an important aspect of host response. Nonetheless, it also contributes to the pathogenesis of many chronic diseases such as chronic asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis [107] , certain cancers and neurodegenerative diseases [13] . As such, when inflammation is excessive or prolonged, it can be harmful [107] .

Macrophages are a major source of pro-inflammatory mediators like nitric oxide (NO), prostaglandin E2 (PGE2), and pro-inflammatory cytokines like TNF-α, (IL-6), interleukin-1β (IL-1β) and ROS. NPs’ anti-inflammatory activity is based on modulation of macrophages function [108] . However, there are not many reported studies [13] . Pheophytin a, from E. prolifera, suppressed the inflammatory response in mouse macrophages [109] . Fucoxanthin exhibits potent anti-inflammatory activity in vitro and in vivo, in response to bacterial lipopolysaccharides (LPS) [110] . The treatment with this compound reduced the production of NO and PGE2 by inhibiting NO synthase (iNOS) and cyclooxygenase 2 (COX-2) expressions. Moreover, the release and expression of TNF-α, IL-6 and IL-1β were attenuated in a dose-dependent manner [111] . The anti-inflammatory effects were due to the suppression of nuclear factor kappa B(NF-kB) and the phosphorylation of mitogen activated protein Kinases (MAPKs) [112] .

During inflammatory diseases, including chronic wound, chronic leg ulcers and rheumatoid arthritis, connective tissue is destructed. This occurs because of the continuous supply of inflammatory cells and exacerbated production of inflammatory cytokines and matrix proteinases. Fucoindan from Ascophyllum nodosum was able to modulate connective tissue proteolysis [113] .

Fucoidan from E. cava inhibit NO and PGE2 production, by suppressing the expression of iNOS and COX-2, in a dose-dependent manner [114] [115] . E. cava also suppressed TNF-α, IL-6 and IL-1β in LPS stimulated murine microglia (BV2) cells. This was achieved by blocking NF-kB and MAPKs activation [116] [117] . Moreover, fucoidans from Laminaria japonicaon and from Fucus vesiculosus presented anti-in- flammatory activity. The first ones inhibited NO production and expression, and the others inhibited the excessive production of NO and PGE2 by suppressing the expression of iNOS and COX-2 [115] .

Selectin family contributes to the interactions of leucocytes and platelets at the side of vascular injury. This enhances inflammatory reactions during arterial response to injury [118] . Fucoindan inhibit the interaction of selectin with its ligands [119] - [122] , reducing inflammation process at early stages [22] .

Although these results indicate that fucoidans have anti-inflammatory activities, others SP may act on the opposite direction. Carrageenan, from red marine algae, is a potent inflammatory in rodents. It leads to the production of TNF-α by mice leucocytes, in response to bacterial LPS [123] . Furthermore, some carrageenans induce potent macrophage activation [124] while others carrageenans and fucoidans inhibit macrophage functions [125] [126] . Moreover, SP from Porphyra yezoensis and Garcilaria verrucosa stimulate phagocytosis and respiratory burst in mouse macrophages in vitro and in vivo [127] [128] . In addition, SP from Ulva rigida induced an increase in the expression of several chemokines and interleukins and the production of nitrite. It also stimulated macrophage secretion of PGE₂ and induced an increase in COX-2 and nitric oxide synthase-2 (NOS-2) expression [129] .

Bioactive peptides have also been reported for the induction and stimulation of the immune system [130] . Most peptides are encrypted in the parent proteins in the algae, and during gastrointestinal digestion, they might be released [131] . Hence, protein hydrolysates have been widely used to enhance the nutritional and functional values of the food [132] . Protein hydrolysate from the microalga Chlorella vulgaris was obtained by the pancreatic enzyme. Its oral administration to mice, during 8 days after 3 days of fasting period, resulted in an increase up to 128% of the lymphocyte pool when com- pared to the control group. Moreover, mononuclear phagocyte system and both humoral and cell mediated immune functions were increased. This included an increase on the functional activities of macrophages, a stimulation of T-dependent antibody responses and reconstitution of delayed-type hypersensitivity (DTH) [133] . The hydrolyzate from E. cava, obtained by protease, enhanced the proliferation effect of splenocytes in mice, including lymphocytes, monocytes and granulocytes. In addition, the number of CD4⁺T cells, CD8⁺T cells and CD45R/B220⁺B cells were markedly increased compared to controls which were untreated. Furthermore, the mRNA expression and production of Th-1 type cytokines, like TNF-α and INF-γ, were down regulated and thus Th-2 type cytokines, including IL-4 and IL-10, were up regulated [134] .

3.4. Anti-Obesity Activity

Obesity is a chronic metabolic disorder that might be defined as excessive body weight in the form of fat. It is caused by an imbalance between body intake and expenditure. Obesity is associated with various diseases particularly heart disease, type 2 diabetes, obstructive sleep apnea, certain types of cancer and osteoarthritis [135] - [137] . Fur- thermore, this disorder keeps increasing in many industrialized and developing countries, affecting teen and seniors [138] . Until the age of 75, being obese or overweight is more prevalent than malnutrition [139] . However, over the age of 75, eating less in or- der to lose weight could result in nutrient deficiencies which may cause more problems than being overweight [140] .

Fucoxanthin from Undaria pinnatifida and fucoxanthinol inhibited the differentiation of 3T3-L1 preadipocytes into adipocytes [141] . This effect might be achieved by down-regulation of adipogenic transcription factors, such as peroxisome proliferator- activated receptor-γ [13] . Moreover, fucoxanthin and neoxantin were reported to suppress adipocyte differentiation [142] . Uncoupling protein 1 (UCP1) is a mitochondrial protein that dissipates energy through uncoupling of oxidative phosphorylation. This leads to the production of heat instead of ATP [143] . A nutrigenomic revealed that fucoxanthin induces UCP1 expression on white adipose tissue, which is the predominate type of adipose tissue in humans. However, UCP1 is known to be exclusively in brown adipose tissue [13] [143] . Nonetheless, further efforts are needed to better understand the molecular mechanisms and the intracellular signaling pathways underlying UCP1 induction by fucoxhanthin [13] . According to these results, NPs are potential candidates to be used, by food and pharmaceutical, in treatment or prevention of obesity [13] .

Fucoidan from Fucus vesiculosus increased the expressed protein levels of total hormone sensitive lipase (HSL) and of phosphorylated-HSL, its activated form. It also decreased insulin-induced 2-deoxy-D-[3H] glucose uptake. These effects lead to stimulation of lipolysis. Hence, fucoidan from Fucus vesiculosus inhibit lipid accumulation through the regulation of lipolysis in 3T3-L1 adipocytes [144] .

The high soluble dietary fiber content of seaweeds helps slow down digestion and caloric absorption and moderate appetite through delaying gastric emptying and absorption in the small intestine [145] . However, this is difficult to prove in humans [14] .

3.5. Anti-Diabetic Activity

Type 2 diabetes mellitus (DM) is more common in older people [146] . One of the reasons is because aging its associated with a reduced ability to metabolize glucose from food [147] . Moreover, it is related to lifestyle and obesity, particularly central adiposity [146] . In older people, increased abdominal obesity can cause metabolic changes leading to insulin resistance, which is a risk factor for the development of type 2 DM [148] .

Diet is essential in the treatment of diabetes and proper nutrition is essential to prevent complications [149] . However, the compliance with diabetic recommendations is low, because it is not easy to follow [150] . Recently, functional foods have appeared as new means to help maintain proper nutrition, in cases of chronic diseases such as diabetes [151] .

Dietary fucoxanthin has been reported for its anti-obesity and anti-diabetic effects [152] - [154] . It attenuates the weight gain of white adiposite tissue (WAT) of diabetic/ obese KK-A(y) mice. When these mice were fed with fucoxanthin, mRNA expression of monocyte chemoattractant protein-1 (MPC-1) and TNF-α, in perigonadal and mesenteric WATS, were markedly reduced compared to control mice. MPC-1 and TNF-α are considered to induce insulin resistance. These parameters were not altered on lean C57BL/6J mice. In addition, fucoxanthin also decreased mRNA expression levels of interleukin-6 (IL-6) and plasminogen activator inhibitor-1 in WAT of KK-A(y) mice [153] .

Fucoxanthiol, the metabolite of fucoxanthin in WAT, attenuated TNF-α induced, MPC-1 and IL-6 mRNA overexpression. According to these results, fucoxanthin regulates m RNA expression of inflammatory adipocytokines involved in insulin resistance on diabetic/obese KK-A(y) mice but not on lean C57BL/6J mice [152] .

On another study, mice were fed with 0.2% of fucoxanthin for 4 weeks. This diet attenuated the gain of WAT in KK-A (y) mice, with increasing uncoupling protein-1 (UCP1) expression when compared to the control mice. The blood glucose and plasma insulin concentrations were also decreased in KK-A(y) mice. Finally, mRNA expressions of leptin and TNF-α were down-regulated [153] .

Wakame (Undaria pinnatifida) is seaweed with fucoxanthin-rich lipids (WLs). The anti-obesity and anti-diabetic effects of these compounds were examined on mice with high fat (HF) diet-induced obesity. The HF diet followed by WL diet (HF-WL diet) suppressed body weight and WAT gain. The hyperglycemia, hyperinsulinemia and hyperleptinemia, that were also a result of HF diet, were normalized in FH-WL diet fed group. In addition, the FH-WL diet promoted mRNA expression of β-3 adrenergic- receptor in WAT, and glucose transporter 4 (GLUT-4) mRNA in skeletal muscle tissue. Given these results, the authors claim that there is a “biochemical and nutritional basis for the application of fucoxanthin-rich WLs as functional foods to prevent obesity and diabetes-related disorders” [154] .

Postprandial hyperglycemia represents a direct and independent risk for cardiovascular disease [155] and it is implicated in the development of type 2 diabetes. Furthermore, it can induce the elevation of glycated haemoglobin (HbA1c), contributing to the development of macro and microvascular problems [156] . Postprandial hyperglycemia can be treated through delaying the digestion of carbohydrates [157] . This can be achieved by inhibiting enzymes responsible for carbohydrate digestion like α-amylase and α-glucosidase [158] .

The extract from the brow algae ezoishige (Pelvetia babingtonni de Toni) inhibited the rat-intestinal α-glucosidase in vitro. Moreover, its oral administration with sucrose significantly suppressed the postprandial elevation of the blood glucose level, compared with the control. According to these results and given the fact that ezoishige is an underutilized algae, it could be considered as a promising functional food material for controlling the blood glucose level, preventing and/or reducing the risk of diabetes and obesity [159] . Acophyllum nodosum and Grateloupia elliptica extracts also inhibited α-glucosidase activity [160] [161] .

Phlorotannins from Ecklonia cava, especially dieckol, were able to significantly inhibit rat-intestinal α-glucosidase and porcine pancreatic α-amylase [162] . Furthermore, phlorotannins are also inhibitors of aldose reductase. This enzyme catalyzes glucose to sorbitol in cells. This activity is important because the accumulation of sorbitol in cells leads to various chronic complications of diabetes like cataracts, neuropathy and retinopathy [35] .

3.6. Neuroprotective Effect

Neurodegenerative diseases are expected to surpass cancer and be the second most common cause of death among elderly by 2040s [163] [164] . For this reason, a great deal of attention has been expressed regarding the effectiveness and the safeness of neuroprotective agents [8] .

Marine algae have been reported to present biological activities and neuroprotective effects, including antioxidant, anti-neuroinflammatory, cholinesterase inhibitory activity and inhibition of neural death. For this reason, they have been recognized for their potential as neuroprotectors, as part of pharmaceuticals and functional foods [8] .

The central nervous system presents high lipid content and high oxygen consumption, which makes it more sensitive to oxidative stress than other parts of our body [165] . Oxidative stress in the CNS involves excitotoxicity and apoptosis, which are the two main causes of neural death. Moreover, it has been implicated in the progression of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), among others [166] [167] . The anti-oxidant activity of marine alga has been reported by different scientists and it has been already discussed. However, there are some studies, regarding this activity, that suggest that marine algae are useful candidates to protect specifically the CNS against oxidative degradation. Neorhodomela aculeate scavenged DPPH and completely suppressed lipid peroxidation induced by H₂O₂ in rat brain homogenate [168] . Halimeda incrassata and Bryothamnion were reported as potent ROS scavengers in mouse hypothalamic (GT1-7) cells [169] ; Moreover, Fucoxanthin from wakame was able to attenuate cell damage in cortical neurons during hypoxia and oxygen reperfusion [170] . Because ROS generation is considered to occur after hypoxia and re-oxygenation, through which free radicals damage neurons, it may assume that fucoxanthin’s neuroprotective is mainly based on its scavenging activity [13] . The same compound, isolated from H. fusiformis inhibited the ex- pression of N-myc and cell cycle progression of GOT0 cells, a human neuroblastoma cell line [171] . The phlorotannin dieckol was able to scavenge ROS production in murine microglia (BV2) cells [172] . Sulphated polysaccharides were also discussed for their anti-oxidant activity. However, its activity against oxidative stress in the CNS has not been demonstrated yet [8] .

In order to use these compounds to slow down the progression of neurodegenerative diseases in populations that are at high risk, such as the elderly, it has to be determined if they can be used as prophylactic neuroprotective agents [8] .

Inflammation is the pathophysiological mechanism underlying neurodegenerative diseases [173] . Although there are many cells that contribute to inflammation-mediated neurodegeneration, microglia is critical components of the immunological insult to neurons [174] . The activation of these immune cells leads to the production of pro- inflammatory and neurotoxic factors that are sufficient to induce neurodegeneration in a rat model. Moreover, their activation and excessive amounts of mediators release by microglia have been observed during the pathogenesis of PD, AD and MS [175] [176] . Among the mediators released by microglia, the most cytotoxic ones are NO and PGE2, in the innate response in the CNS [177] [178] . Furthermore, NO generated by iNOS causes injury and cell death of neuron and oligodendrocytes in the CNS and so it is implicated in the pathogenesis of many neurodegenerative diseases [177] [179] [180] . As described, some marine algae were reported to have anti-inflammatory effects, some of them regarding BV2 cells, NO and PGE2. N. aculeate decreased the production of NO and iNOS expression in interferon-gamma (INF-γ) stimulated BV2 cells [181] . The methanolic extracts of U. conglobata suppressed the expression of pro-inflammatory enzymes, iNOS and COX-2, which were responsible for the large production of NO and PGE2, respectively [182] [183] . However, further studies are needed, including clinical trials, regarding anti-neuroinflammatory activity [8] .

Alzheimer’s disease has been associated with a deficiency in the brain neurotransmitter acetylcholine (Ach) [184] . Therefore, inhibition of the enzyme that catalyzes the breakdown of Ach, acetylcholinesterase (AChE), may be a realistic approach to the symptomatic treatment [185] . Some algae have been reported for their AChE inhibitory activity such as Ecklonia stolonifera and Ishige okamurae. Some of the compounds in- volved were eckol, dieckol, 2-phloroeckol and 3-phloroeckol from the first algae and 6,6-bieckol from the other algae [186] [187] .

Regarding neural death, fucoidan from Fucus vesiculosus have been reported for its capacity to protect rat cholinergic neural death induced by amyloid beta₁₋₄₂ (Aβ₁₋₄₂) [188] . The treatment with fucoidan blocked the activation of caspase-9 and caspase-3, which may mediate the terminal stages of neural apoptosis [189] . Hence, inhibition of neural death by fucoidan may occur mainly through apoptotic inhibition [8] .

3.7. Other Biological Activities

Seaweeds have a higher content in soluble dietary fibers than terrestrial plants [190] . Soluble fibers effects include water binding, fecal bulking and digestive transit time decrease, which benefits gut health [191] [192] and indirectly prevent colon cancer [193] .

Dietary fibers also support the reduction of cholesterol levels. The Sp from Ulva pertusa reduced serum triglycerides (Tg), total cholesterol and low density lipoprotein cholesterol (LDL-cholesterol). It also increased high density lipoprotein (HDL-cholesterol) in mice. The anti-hyperlipidemic activity was related to the molecular weight of Ulvan fractions [193] . Moreover, porphyran from Porphyra Yezoensis reduced apolipoprotein B100 (ApoB100) secretion [194] which levels were positively related to cardiovascular disease [195] . The reduction of ApoB100 secretion is achieved mainly through the suppression of lipid synthesis in human liver derived cells [194] .

Furthermore, fucoidan from Cladosiphon okamuranus was reported to protect gastic mucosa against acid and pepsin. Hence, it could be developed as a potential anti-ulcer ingredient in functional foods [196] [197] .

4. Conclusions

Functional foods can be particularly important in older people. They can have a role in special nutrient intake and in reducing the risk of chronic conditions [6] . Algae can be a source of new compounds that could be used as functional ingredients [5] . They pro- duce a great variety of biological active components that cannot be found in other organisms [12] , and research reports on their therapeutic properties are numerous [5] .

The studies suggest that NP [13] , phlorotannins [36] , SP [17] and proteins [130] from seaweeds, and microalgae have potential to be a part of new functional foods. However, further studies are needed, for example studies in human subjects, as in the case of SP [17] , or large-scale controlled studies and human studies in order to investigate algae neuroprotective activities [8] . Moreover, once usefulness is demonstrated it will be necessary to consider other aspects as ingredients extraction and purification, their production at industrial scale, algae growing, among others [5] .

Acknowledgements

The authors wish to thank to “Projeto Estratégico-RG-Centro-177-3717 da FCT” (Portugal).

Conflicts of Interest

The authors declare no conflicts of interest.

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