PMC:7601109 / 6144-26669 JSONTXT

{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T4","span":{"begin":673,"end":678},"obj":"Body_part"},{"id":"T5","span":{"begin":998,"end":1003},"obj":"Body_part"},{"id":"T6","span":{"begin":2713,"end":2718},"obj":"Body_part"},{"id":"T7","span":{"begin":2793,"end":2797},"obj":"Body_part"},{"id":"T8","span":{"begin":7942,"end":7946},"obj":"Body_part"},{"id":"T9","span":{"begin":14545,"end":14551},"obj":"Body_part"},{"id":"T10","span":{"begin":16708,"end":16713},"obj":"Body_part"},{"id":"T11","span":{"begin":16715,"end":16720},"obj":"Body_part"},{"id":"T12","span":{"begin":16737,"end":16742},"obj":"Body_part"},{"id":"T13","span":{"begin":17682,"end":17687},"obj":"Body_part"},{"id":"T14","span":{"begin":18496,"end":18501},"obj":"Body_part"},{"id":"T15","span":{"begin":18593,"end":18597},"obj":"Body_part"},{"id":"T16","span":{"begin":19664,"end":19669},"obj":"Body_part"},{"id":"T17","span":{"begin":19850,"end":19855},"obj":"Body_part"},{"id":"T18","span":{"begin":20480,"end":20485},"obj":"Body_part"}],"attributes":[{"id":"A4","pred":"uberon_id","subj":"T4","obj":"http://purl.obolibrary.org/obo/UBERON_0002548"},{"id":"A5","pred":"uberon_id","subj":"T5","obj":"http://purl.obolibrary.org/obo/UBERON_0007113"},{"id":"A6","pred":"uberon_id","subj":"T6","obj":"http://purl.obolibrary.org/obo/UBERON_0007113"},{"id":"A7","pred":"uberon_id","subj":"T7","obj":"http://purl.obolibrary.org/obo/UBERON_2000006"},{"id":"A8","pred":"uberon_id","subj":"T8","obj":"http://purl.obolibrary.org/obo/UBERON_0000014"},{"id":"A9","pred":"uberon_id","subj":"T9","obj":"http://purl.obolibrary.org/obo/UBERON_0001836"},{"id":"A10","pred":"uberon_id","subj":"T10","obj":"http://purl.obolibrary.org/obo/UBERON_0000955"},{"id":"A11","pred":"uberon_id","subj":"T11","obj":"http://purl.obolibrary.org/obo/UBERON_0002107"},{"id":"A12","pred":"uberon_id","subj":"T12","obj":"http://purl.obolibrary.org/obo/UBERON_0002530"},{"id":"A13","pred":"uberon_id","subj":"T13","obj":"http://purl.obolibrary.org/obo/UBERON_0006612"},{"id":"A14","pred":"uberon_id","subj":"T14","obj":"http://purl.obolibrary.org/obo/UBERON_0000165"},{"id":"A15","pred":"uberon_id","subj":"T15","obj":"http://purl.obolibrary.org/obo/UBERON_0000014"},{"id":"A16","pred":"uberon_id","subj":"T16","obj":"http://purl.obolibrary.org/obo/UBERON_0001977"},{"id":"A17","pred":"uberon_id","subj":"T17","obj":"http://purl.obolibrary.org/obo/UBERON_0007113"},{"id":"A18","pred":"uberon_id","subj":"T18","obj":"http://purl.obolibrary.org/obo/UBERON_0007113"}],"text":"2. Apitherapy as a Possible Complementary Treatment for Sarcopenia\nRock paintings from the Stone Age portray consumption of bee products by humans [27]. The first evidence of human usage of bee products for therapeutic and cosmetic purposes dates back 6000 years in ancient Egypt and later in China, Greece, and Rome [27,28,29,30]. Current research interest is directed toward the use of natural substances, including bee products, as potential pharmaceuticals to modify disease progression [31]. The term “apitherapy” describes a category of complementary and alternative medicine that comprises therapeutic use of various bee products including apilarnil (atomized drone larva) to prevent and treat illnesses [30].\nBee workers of either Apis mellifera or Apis cerana species—the former is common in Europe, Asia, Africa, and America while the latter exists only in southern and southeastern Asia—produce and store multiple bioactive substances [32]. Royal jelly, propolis, bee pollen, honey, bee venom, bee bread, and bee wax are common products of the bee hive. They all (to a varying degree) possess multiple health promoting properties due to their high content of natural antioxidants such as flavonoids, phenols, or terpenoids [28,32]. Research documents variability in contents and effects of every single bee product, mainly due to the influence of bee species, botanical origin, geographic location, season, extraction, and handling procedures [2,28].\nSeveral lines of evidence describe anti-aging effects of royal jelly, bee pollen, and propolis both in humans and laboratory animals [2,33,34,35]. These three products are widely used as dietary supplements [36,37,38,39]. In the meantime, the literature gives examples of numerous dietary supplements that could successfully prevent or alleviate the progression of muscle mass loss in old age [40,41,42]. Bee products represent a part of this interventional strategy. However, the extent to which bee products can affect sarcopenia as well as understanding of their underlying mechanism of action are far from being clear. Therefore, we conducted this review with the aim of investigating the anti-aging properties of these products with a focus on skeletal muscle functioning in advanced age. In this respect, we reviewed animal and human studies investigating effects of the aforementioned products on skeletal muscle aging and elaborated on different mechanisms underlying these effects. Studies included in this review were retrieved by searching PubMed and Google scholar using a combination of terminologies of “sarcopenia, muscle wasting, muscle mass, lean body mass, skeletal muscle, motor” with “royal jelly, honey, bee pollen, propolis, bee venom, bee bread, bee wax, chrysin, apamin, caffeic acid phenethyl ester”. Snow ball manual search using reference lists of retrieved studies was also conducted. This search resulted in a number of studies, which addressed muscle wasting and related dynamics through the use of three bee products, namely royal jelly, bee pollen, and propolis. Figure 1, Panel A and Panel B, summarizes the chemical composition and biological properties of these bee products while this section elaborates on these products in depth.\n\n2.1. Royal Jelly: Its Constituents, Biological, and Pharmacological Activities\nRoyal jelly is a thick, milky, white-yellowish, acidic colloid substance secreted from the hypopharyngeal and mandibular salivary glands of young nurse honey bees (5–15 days old) [32,43]. In general, fresh royal jelly mostly consists of water (67% w/w) in addition to carbohydrates (16%), proteins and amino acids (12.5%), fat (5%), and many other elements [32]. However, royal jelly content of these substances noticeably varies depending on numerous factors like botanical source, bee species, bee artificial feeding, weather, season, location, method of processing, and the like [2,44].\nProtein is the most copious active element in royal jelly, representing half the weight of its dry matter [2]. It vastly comprises nine 49–87 kDa water-insoluble proteins, known as major royal jelly proteins 1–9 (MRJPs1-9) [2,45]. MRJPs constitute more than 80% of royal jelly protein content, and MRJPs1–5 constitute 82–90% of all MRJPs. MRJPs contain 400–578 amino acids that contribute to the antioxidant effect of royal jelly as well as its role in cell proliferation, cell adhesion, cell growth, and immunity [46,47]. Novel non-MRJPs proteins have been newly discovered [48]. Royalisin, jelleines, and aspimin are examples of other proteins that exist in royal jelly, albeit in small amounts. These proteins as well as MRJPs demonstrate strong antimicrobial and bactericidal activities even against the most drug-resistant bacterial strains such as methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, vancomycin-resistant Enterococci, as well as extended-spectrum β-lactamase-producing Proteus mirabilis and Escherichia coli [28,29].\nCarbohydrates (e.g., fructose, glucose maltose, trehalose, melibiose, ribose, and erlose) constitute 7.5–16% or royal jelly content [49]. Reducing sugars in royal jelly are thought to contribute to its epigenetic effect through the activation of insulin-like growth factor 1 (IGF-1) and mammalian target of rapamycin (mTOR) signaling cascades. Thus, they stimulate caste differentiation of Apis mellifera larvae into queens by increasing intake of food and key nutrients [50].\nLipids make up 7–18% of the dry weight of royal jelly. This fraction largely comprises a group of unique and rare saturated or monounsaturated short and medium chain fatty acids that are terminally or internally hydroxylated with terminal mono- or dicarboxylic acid functions [2,28]. The vast majority of royal jelly fat content (80–85%) consists of short hydroxyl fatty acids such as trans-10-hydroxy-2-decenoic acid (10-HDA), which exists only in royal jelly; and therefore, it is known as royal jelly acid or queen bee acid [28,49,51]. 10-HDA is one of the most potent bioactive elements in royal jelly expressing strong anti-aging, neuroprotective, antiproliferative, antimicrobial, antioxidant, anti-inflammatory, and epigenetic effects [52,53,54,55,56,57,58]. In addition, the lipid fraction of royal jelly contains phenolic acids (4–10%), wax (5–6%), steroids (3–4%), and phospholipids (0.4–0.8%) [49].\nA wide range of minor constituents and bioactive compounds exist profusely in royal jelly such as acetylcholine, nucleotides (adenosine, guanosine, adenosine tri-phosphate (ATP), adenosine monophosphate (AMP)), minerals (iron, sodium, calcium, potassium, zinc, magnesium, manganese, and copper), amino acids (8 out of 9 essential amino acids Val, Leu, Ile, Thr, Met, Phe, Lys, and Trp), vitamins (retinol (A), ascorbic acid (C), tocopherol (E), riboflavin (B2), niacin (B3), and other B vitamins), esters, aldehydes, ketones, alcohol, and minor heterocyclic compounds [2,28,49,59,60,61]. It is worth noting that royal jelly loses most of its bioactive ingredients and biological properties when stored at a temperature of 5 °C or higher. Therefore, freezing is the best method to store royal jelly [62]. Enzymatic treatment of royal jelly removes allergen proteins and enhances its nutrient content in addition to improving its digestibility and absorption in the gut without altering its freshness [2,59].\nRoyal jelly has been historically used as a beautifying agent by famous queens such as Cleopatra, and it is still involved in the cosmetic industry [29,56]. Its rich content of bioactive compounds grants it a plethora of diverse health benefits such as antioxidant, anti-inflammatory, neurotrophic, hypotensive, antidiabetic, antilipidemic, antirheumatic, anticarcinogenic, anti-fatigue, antiadipogenic, and antimicrobial activities [43,45,63]. Therefore, it is widely used to treat multiple serious conditions including diabetes, hypertension, hyperlipidemia, cancer, skin diseases, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease [2,43,46,59,64]. In addition, bee queens (which enjoy long lifespan as well as super fertility and physical qualities) consume royal jelly throughout their entire lives, and royal jelly is considered a promising anti-aging nutraceutical that can positively enhance fertility and improve body composition [2].\n\n2.2. Propolis: Its Constituents, Biological, and Pharmacological Activities\nPropolis, also known as bee glue, is a sticky wax-like substance that constitutes a mixture of bee salivary secretions, bee wax, and resinous sap occurring in the bark and leaf-buds of specific plants [37,65]. It comes in green, red, brown, or black colors based on the collected local flora [66]. The word propolis comprises two Greek words “pro” and “polis”, which in order mean “in front of or at the entrance to” and “community or city”. Propolis is a hive-defensive substance, which bees use to protect and repair their hives [67].\nPropolis is a unique product of a complex composition that comprises more than 420 chemical substances [37,68]. Nonetheless, its composition and biological activities vary considerably depending on its botanical and geographical origins as well as the time of harvesting [38,65,67]. Propolis is rich in oxyprenylated phenylpropanoids—secondary metabolites from plants, fungi, and bacteria [69]—such as 7-isopentenyloxucoumarin, boropinic acid, 4-geranyloxyferulic acid, and auraptene. The last two exist in raw Italian propolis at high concentrations: 107.12 and 145.37 μg/g of dry propolis, respectively. Flavonoids, a large group of phenolic compounds, are abundant in Italian propolis, and they are differentiated into several groups including flavanones (e.g., naringenine, 4.4 mg/g), flavones (e.g., apigenine, 1.7 mg/g), flavonols (e.g., galaning, 0.9 mg/g), tannins (e.g., gallic acid 8.4 mg/g), catechins (expressed as (+)-catechin 0.4 mg/g, and caffeic acid and its esters (expressed as caffeic acid, 9.2 mg/g) [69]. The most profuse flavonoids in ethanolic extracts of Brazilian propolis are artepillin C (38.6 mg/g), coumaric acid (10.6 mg/g), and kaempferide (12.6 mg/g) [70]. Key other constituents of propolis include polyphenol (e.g., phenolic acids and aromatic esters), phenolic aldehydes, terpenoids, ketones, enzymes (e.g., α- and β-amylase), vitamins (e.g., thiamin (B1), riboflavin (B2), pyridoxine (B6), ascorbic acid (C), tocopherol (E)), minerals (e.g., calcium, potassium, magnesium, iron, sodium, barium) essential oils, alcohol, fatty acids, β-steroids, and many other elements [37,38,67,68,71].\nThe attention of several drug targeting studies has recently been focused on the therapeutic activities of individual bioactive compounds in propolis [65,68]. Flavonoids comprise the majority of mostly studies bioactive substances in propolis. Chrysin (5,7-dihydroxyflavone) is a flavonoid that exists in certain mushrooms, flowers (e.g., blue passion flower), and in other bee products (e.g., honey). It expresses anti-inflammatory, antioxidant, anti-proliferative, and neuroprotective effects [72]. Caffeic acid phenethyl ester (CAPE), a derivative of hydroxycinnamic acid, expresses anti-oxidant, immunomodulatory, anti-inflammatory, antiviral, and ant-neoplastic properties [73,74,75]. Pinocembrin (5,7-dihydroxyflavanone) is the most copious flavonoid in propolis—1 g of balsam/an ethanolic extract from poplar propolis found in Spain contains up to 606–701 mg of pinocembrin [76]. It exists in numerous plants (e.g., Eucalyptus and Populus). It exhibits anti-inflammatory, antioxidant, antimicrobial, and antiproliferative activities [77,78].\nEssential/volatile oils are major bioactive constituents of propolis, and they contribute to its special aroma [79,80]. They also, partially, contribute to the strong antimicrobial, antioxidant, and anticancer activities of propolis [79,81,82]. The volatile fraction of propolis varies in each sample even within a single country due to plant source and climate [79]. For instance, cumulative knowledge shows that volatile oils in propolis found in countries surrounding the Mediterranean depend mainly on the botanical origin. They primarily comprise poplar-derived compounds (e.g., benzoic acid and its esters and oxygenated sesquiterpene β-eudesmol) and conifer-derived compounds such as the hydrocarbon monoterpene α-pinene [80]. Interestingly, the number of volatile compounds derived from a single type of propolis is also reported to vary according to extraction techniques. In this regard, reports from China show that traditional hydrodistillation, steam-distillation extraction, and dynamic headspace sampling could characterize around 12, 40 and 70 type of volatile components of propolis, respectively [79]. Moreover, the level of antimicrobial activity of volatile compounds of propolis greatly depends on their extent of purification [82].\nThanks to its countless bioactive elements, propolis enjoys a range of versatile biological and pharmacological properties including antimicrobial, antiviral, antifungal, antioxidant, anti-inflammatory, antineoplastic, antiaging, and cytostatic properties. In addition, it is considered a perfect natural food preservative due to its antimicrobial activity [35,38,65,66,68,71]. Because of its enormous health-promoting activities, propolis is widely used as a dietary supplement in many countries, especially in Japan [37,38,39].\nPropolis is not suitable for use in its crude state since it may contact harmful materials e.g., asphalt from the road [68]. Using solvents like ethanol, glycerol, chloroform, ether and acetone or water is necessary to get rid of hazardous substances and to increase its yield of bioactive compounds [67,68]. Although water may be a cheap solvent, propolis has poor solubility in water. Therefore, propolis water extracts are 10-fold lower in their phenolic contents than ethanol extracts. In addition, they retain the strong flavor and aroma of propolis [68]. Moreover, propolis contains allergenic components: caffeic acids derivates (e.g., 3-methyl-2-butenyl caffeate and phenylethyl caffeate), as well as benzyl salicylate and benzyl cinnamate [80]. Therefore, propolis use/consumption should be contraindicated in individuals with known allergies.\n\n2.3. Bee Pollen: Its Constituents, Biological, and Pharmacological Activities\nBee pollen is an api-material that originally comprises male gametophytes or spermatophytes of flowers, which stick to bee body. Bee workers mix these floral pollens with honey, nectar, and bee saliva. The latter is rich in various enzymes e.g., amylase, catalase, as well as lactic acid bacteria, which cause pollen fermentation [36,83,84]. Hence, the tiny wind pollen grains collected by bees aggregate together to form granules or pellets of 1.4–4 mm in size [84].\nIn addition to water, which in order constitutes 20–30% and 6–8% of the content of recently collected and dried bee pollen, bee pollen contains around 200 chemical compounds. Like other bee products, its composition varies considerably according to botanical origin. Carbohydrates account for the most abundant ingredient (18.50–84.25%), and reducing sugars such as glucose, fructose, and sucrose constitute the vastest majority (13–55%). Other major elements include proteins and essential amino acids (5–60%), unsaturated and saturated fatty acids (0.15–31.26%), crude fiber (0.3–20%), nucleic acids (especially RNA), and various minerals (e.g., potassium, phosphorus, calcium, magnesium, zinc, copper, manganese, and iron) [36,83,84,85,86]. In addition, its average total phenolic content is 30.59 mg gallic acid equivalents (GAE)/g, but again it varies considerably based on floral origin (0.69–213.20 mg GAE/g) [86]. Moreover, bee pollen is abundant in both water- and fat-soluble vitamins e.g., β-carotene (vitamin A precursor), ascorbic acid (C), tocopherol (E), folic acid (B9), and other vitamin B, especially niacin. Bee pollen contains other elements that still need to be explored (2–5%) [83]. Therefore, bee pollen represents a perfect whole health-promoting food. In fact, comparisons of the percentages of nutrients in bee pollen with daily required intake of an adult individual revealed that few grams of bee pollen can meet daily human nutritional requirements [83,84].\nBee pollen demonstrates various biological properties and therapeutic activities e.g., antioxidant, anti-inflammatory, anti-lipidemic, anticancer, antiallergic, and antimicrobial [36,87]. Existing knowledge emphasizes its antiaging effects: it reduced the production of age-related pigment known as lipofuscin (induced by oral peroxidized corn oil or intravenous alloxan injection) in cardiac muscle, brain, liver, and suprarenal gland in aged mice (reviewed in [34]).\nThe composition of bee pollens depends primarily on its botanical source since nutrient contents (e.g., polyphenols) of pollen grains, which support their survival and fusion with female gametes, vary between different plants [83,84]. Storage conditions are of great importance were it to retain its biological activities. Bee pollen should be consumed fresh soon after collection. Most of its major elements (reducing sugars, total proteins, vitamin C, and provitamin A) are destroyed at 40 °C. Lyophilization damages its vitamin content while freezing is recommended for the storage of bee pollen since it does not affect its chemical structure [83].\nDry pollen pellets resist decay due to their tough outer coat, which comprises two layers made of cellulose and sporopollenin [88,89]. However, ingestion of bee pollen by humans may not yield its optimal nutritional value because the hard sporopollenin shell hinders access of digestive secretions to the nutrient-rich core of the pellet. Biological, chemical, and mechanical techniques are used to break bee pollen microcapsules in order to enhance its digestibility in the gut. However, these methods may be expensive or ineffective i.e., they degrade important nutrients via enzymatic activity [88,90]. Ultraviolet spectroscopy and high performance liquid chromatography-photo diode array show that processing bee pollen through the use of an edible lipid-surfactant mixture (Captex 355 and Tween 80) increases its yield of polyphenols and flavonoid aglycones [90].\n\n2.4. Safety Profile of Royal Jelly, Propolis, and Bee Pollen\nPropolis exists in a plethora of commercial products that are directly consumed or used by humans e.g., lozenges, soap, toothpastes and mouth wash, creams, gels, cough syrups, wines, cakes, chewing gums, candies, shampoo, chocolate, skin lotions, processed meat, etc. [67]. In addition, royal jelly, bee pollen, and propolis are widely used as dietary supplements in many parts of the world [36,37,38,39]. Existing knowledge denotes no adverse effects from their consumption either in rodents or in humans [39,66]. The safety of pinocembrin, a flavonoid available in propolis and an approved drug in China, is documented since its elimination from the body is rapid [91]. The safety profile of bee pollen (both crude and processed) has been empirically tested. Oral consumption of bee pollen (up to 2 g/kg body weight) expressed no allergic reactions in mice including behavioral changes, salivation, diarrhea, respiratory or autonomic responses, restlessness, convulsions, tremors, or death [90]. In fact, the German Federal Board of Health acknowledges bee pollen as an official medicine [36].\nSeveral lines of evidence support the anti-allergic effect of propolis and royal jelly. This effect involves inhibiting mast cell degranulation, suppressing cysteinyl-leukotriene release, as well as reducing serum histamine, IgG, and IgE levels in various allergic conditions by suppressing histamine H1 receptor [37,39,92]. Nevertheless, rare allergic reactions to bee products other than bee venom are documented in the literature. They are most frequent in small children [80,93]. Examples of such reactions comprise contact dermatitis in beekeepers following the handling of propolis, as well as contact stomatitis and oral mucositis after the usage of lozenges containing propolis [80]. Hence, bee products should be used with caution, especially in people with known allergies, pregnant and lactating women, and small children [61]. In addition, bee products can be safely consumed after adequate processing. Processing involves removal of known allergens such as enzyme treatment of royal jelly and filtration of bee venom by stepped-gradient open column [2,94]."}

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Apitherapy as a Possible Complementary Treatment for Sarcopenia\nRock paintings from the Stone Age portray consumption of bee products by humans [27]. The first evidence of human usage of bee products for therapeutic and cosmetic purposes dates back 6000 years in ancient Egypt and later in China, Greece, and Rome [27,28,29,30]. Current research interest is directed toward the use of natural substances, including bee products, as potential pharmaceuticals to modify disease progression [31]. The term “apitherapy” describes a category of complementary and alternative medicine that comprises therapeutic use of various bee products including apilarnil (atomized drone larva) to prevent and treat illnesses [30].\nBee workers of either Apis mellifera or Apis cerana species—the former is common in Europe, Asia, Africa, and America while the latter exists only in southern and southeastern Asia—produce and store multiple bioactive substances [32]. Royal jelly, propolis, bee pollen, honey, bee venom, bee bread, and bee wax are common products of the bee hive. They all (to a varying degree) possess multiple health promoting properties due to their high content of natural antioxidants such as flavonoids, phenols, or terpenoids [28,32]. Research documents variability in contents and effects of every single bee product, mainly due to the influence of bee species, botanical origin, geographic location, season, extraction, and handling procedures [2,28].\nSeveral lines of evidence describe anti-aging effects of royal jelly, bee pollen, and propolis both in humans and laboratory animals [2,33,34,35]. These three products are widely used as dietary supplements [36,37,38,39]. In the meantime, the literature gives examples of numerous dietary supplements that could successfully prevent or alleviate the progression of muscle mass loss in old age [40,41,42]. Bee products represent a part of this interventional strategy. However, the extent to which bee products can affect sarcopenia as well as understanding of their underlying mechanism of action are far from being clear. Therefore, we conducted this review with the aim of investigating the anti-aging properties of these products with a focus on skeletal muscle functioning in advanced age. In this respect, we reviewed animal and human studies investigating effects of the aforementioned products on skeletal muscle aging and elaborated on different mechanisms underlying these effects. Studies included in this review were retrieved by searching PubMed and Google scholar using a combination of terminologies of “sarcopenia, muscle wasting, muscle mass, lean body mass, skeletal muscle, motor” with “royal jelly, honey, bee pollen, propolis, bee venom, bee bread, bee wax, chrysin, apamin, caffeic acid phenethyl ester”. Snow ball manual search using reference lists of retrieved studies was also conducted. This search resulted in a number of studies, which addressed muscle wasting and related dynamics through the use of three bee products, namely royal jelly, bee pollen, and propolis. Figure 1, Panel A and Panel B, summarizes the chemical composition and biological properties of these bee products while this section elaborates on these products in depth.\n\n2.1. Royal Jelly: Its Constituents, Biological, and Pharmacological Activities\nRoyal jelly is a thick, milky, white-yellowish, acidic colloid substance secreted from the hypopharyngeal and mandibular salivary glands of young nurse honey bees (5–15 days old) [32,43]. In general, fresh royal jelly mostly consists of water (67% w/w) in addition to carbohydrates (16%), proteins and amino acids (12.5%), fat (5%), and many other elements [32]. However, royal jelly content of these substances noticeably varies depending on numerous factors like botanical source, bee species, bee artificial feeding, weather, season, location, method of processing, and the like [2,44].\nProtein is the most copious active element in royal jelly, representing half the weight of its dry matter [2]. It vastly comprises nine 49–87 kDa water-insoluble proteins, known as major royal jelly proteins 1–9 (MRJPs1-9) [2,45]. MRJPs constitute more than 80% of royal jelly protein content, and MRJPs1–5 constitute 82–90% of all MRJPs. MRJPs contain 400–578 amino acids that contribute to the antioxidant effect of royal jelly as well as its role in cell proliferation, cell adhesion, cell growth, and immunity [46,47]. Novel non-MRJPs proteins have been newly discovered [48]. Royalisin, jelleines, and aspimin are examples of other proteins that exist in royal jelly, albeit in small amounts. These proteins as well as MRJPs demonstrate strong antimicrobial and bactericidal activities even against the most drug-resistant bacterial strains such as methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, vancomycin-resistant Enterococci, as well as extended-spectrum β-lactamase-producing Proteus mirabilis and Escherichia coli [28,29].\nCarbohydrates (e.g., fructose, glucose maltose, trehalose, melibiose, ribose, and erlose) constitute 7.5–16% or royal jelly content [49]. Reducing sugars in royal jelly are thought to contribute to its epigenetic effect through the activation of insulin-like growth factor 1 (IGF-1) and mammalian target of rapamycin (mTOR) signaling cascades. Thus, they stimulate caste differentiation of Apis mellifera larvae into queens by increasing intake of food and key nutrients [50].\nLipids make up 7–18% of the dry weight of royal jelly. This fraction largely comprises a group of unique and rare saturated or monounsaturated short and medium chain fatty acids that are terminally or internally hydroxylated with terminal mono- or dicarboxylic acid functions [2,28]. The vast majority of royal jelly fat content (80–85%) consists of short hydroxyl fatty acids such as trans-10-hydroxy-2-decenoic acid (10-HDA), which exists only in royal jelly; and therefore, it is known as royal jelly acid or queen bee acid [28,49,51]. 10-HDA is one of the most potent bioactive elements in royal jelly expressing strong anti-aging, neuroprotective, antiproliferative, antimicrobial, antioxidant, anti-inflammatory, and epigenetic effects [52,53,54,55,56,57,58]. In addition, the lipid fraction of royal jelly contains phenolic acids (4–10%), wax (5–6%), steroids (3–4%), and phospholipids (0.4–0.8%) [49].\nA wide range of minor constituents and bioactive compounds exist profusely in royal jelly such as acetylcholine, nucleotides (adenosine, guanosine, adenosine tri-phosphate (ATP), adenosine monophosphate (AMP)), minerals (iron, sodium, calcium, potassium, zinc, magnesium, manganese, and copper), amino acids (8 out of 9 essential amino acids Val, Leu, Ile, Thr, Met, Phe, Lys, and Trp), vitamins (retinol (A), ascorbic acid (C), tocopherol (E), riboflavin (B2), niacin (B3), and other B vitamins), esters, aldehydes, ketones, alcohol, and minor heterocyclic compounds [2,28,49,59,60,61]. It is worth noting that royal jelly loses most of its bioactive ingredients and biological properties when stored at a temperature of 5 °C or higher. Therefore, freezing is the best method to store royal jelly [62]. Enzymatic treatment of royal jelly removes allergen proteins and enhances its nutrient content in addition to improving its digestibility and absorption in the gut without altering its freshness [2,59].\nRoyal jelly has been historically used as a beautifying agent by famous queens such as Cleopatra, and it is still involved in the cosmetic industry [29,56]. Its rich content of bioactive compounds grants it a plethora of diverse health benefits such as antioxidant, anti-inflammatory, neurotrophic, hypotensive, antidiabetic, antilipidemic, antirheumatic, anticarcinogenic, anti-fatigue, antiadipogenic, and antimicrobial activities [43,45,63]. Therefore, it is widely used to treat multiple serious conditions including diabetes, hypertension, hyperlipidemia, cancer, skin diseases, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease [2,43,46,59,64]. In addition, bee queens (which enjoy long lifespan as well as super fertility and physical qualities) consume royal jelly throughout their entire lives, and royal jelly is considered a promising anti-aging nutraceutical that can positively enhance fertility and improve body composition [2].\n\n2.2. Propolis: Its Constituents, Biological, and Pharmacological Activities\nPropolis, also known as bee glue, is a sticky wax-like substance that constitutes a mixture of bee salivary secretions, bee wax, and resinous sap occurring in the bark and leaf-buds of specific plants [37,65]. It comes in green, red, brown, or black colors based on the collected local flora [66]. The word propolis comprises two Greek words “pro” and “polis”, which in order mean “in front of or at the entrance to” and “community or city”. Propolis is a hive-defensive substance, which bees use to protect and repair their hives [67].\nPropolis is a unique product of a complex composition that comprises more than 420 chemical substances [37,68]. Nonetheless, its composition and biological activities vary considerably depending on its botanical and geographical origins as well as the time of harvesting [38,65,67]. Propolis is rich in oxyprenylated phenylpropanoids—secondary metabolites from plants, fungi, and bacteria [69]—such as 7-isopentenyloxucoumarin, boropinic acid, 4-geranyloxyferulic acid, and auraptene. The last two exist in raw Italian propolis at high concentrations: 107.12 and 145.37 μg/g of dry propolis, respectively. Flavonoids, a large group of phenolic compounds, are abundant in Italian propolis, and they are differentiated into several groups including flavanones (e.g., naringenine, 4.4 mg/g), flavones (e.g., apigenine, 1.7 mg/g), flavonols (e.g., galaning, 0.9 mg/g), tannins (e.g., gallic acid 8.4 mg/g), catechins (expressed as (+)-catechin 0.4 mg/g, and caffeic acid and its esters (expressed as caffeic acid, 9.2 mg/g) [69]. The most profuse flavonoids in ethanolic extracts of Brazilian propolis are artepillin C (38.6 mg/g), coumaric acid (10.6 mg/g), and kaempferide (12.6 mg/g) [70]. Key other constituents of propolis include polyphenol (e.g., phenolic acids and aromatic esters), phenolic aldehydes, terpenoids, ketones, enzymes (e.g., α- and β-amylase), vitamins (e.g., thiamin (B1), riboflavin (B2), pyridoxine (B6), ascorbic acid (C), tocopherol (E)), minerals (e.g., calcium, potassium, magnesium, iron, sodium, barium) essential oils, alcohol, fatty acids, β-steroids, and many other elements [37,38,67,68,71].\nThe attention of several drug targeting studies has recently been focused on the therapeutic activities of individual bioactive compounds in propolis [65,68]. Flavonoids comprise the majority of mostly studies bioactive substances in propolis. Chrysin (5,7-dihydroxyflavone) is a flavonoid that exists in certain mushrooms, flowers (e.g., blue passion flower), and in other bee products (e.g., honey). It expresses anti-inflammatory, antioxidant, anti-proliferative, and neuroprotective effects [72]. Caffeic acid phenethyl ester (CAPE), a derivative of hydroxycinnamic acid, expresses anti-oxidant, immunomodulatory, anti-inflammatory, antiviral, and ant-neoplastic properties [73,74,75]. Pinocembrin (5,7-dihydroxyflavanone) is the most copious flavonoid in propolis—1 g of balsam/an ethanolic extract from poplar propolis found in Spain contains up to 606–701 mg of pinocembrin [76]. It exists in numerous plants (e.g., Eucalyptus and Populus). It exhibits anti-inflammatory, antioxidant, antimicrobial, and antiproliferative activities [77,78].\nEssential/volatile oils are major bioactive constituents of propolis, and they contribute to its special aroma [79,80]. They also, partially, contribute to the strong antimicrobial, antioxidant, and anticancer activities of propolis [79,81,82]. The volatile fraction of propolis varies in each sample even within a single country due to plant source and climate [79]. For instance, cumulative knowledge shows that volatile oils in propolis found in countries surrounding the Mediterranean depend mainly on the botanical origin. They primarily comprise poplar-derived compounds (e.g., benzoic acid and its esters and oxygenated sesquiterpene β-eudesmol) and conifer-derived compounds such as the hydrocarbon monoterpene α-pinene [80]. Interestingly, the number of volatile compounds derived from a single type of propolis is also reported to vary according to extraction techniques. In this regard, reports from China show that traditional hydrodistillation, steam-distillation extraction, and dynamic headspace sampling could characterize around 12, 40 and 70 type of volatile components of propolis, respectively [79]. Moreover, the level of antimicrobial activity of volatile compounds of propolis greatly depends on their extent of purification [82].\nThanks to its countless bioactive elements, propolis enjoys a range of versatile biological and pharmacological properties including antimicrobial, antiviral, antifungal, antioxidant, anti-inflammatory, antineoplastic, antiaging, and cytostatic properties. In addition, it is considered a perfect natural food preservative due to its antimicrobial activity [35,38,65,66,68,71]. Because of its enormous health-promoting activities, propolis is widely used as a dietary supplement in many countries, especially in Japan [37,38,39].\nPropolis is not suitable for use in its crude state since it may contact harmful materials e.g., asphalt from the road [68]. Using solvents like ethanol, glycerol, chloroform, ether and acetone or water is necessary to get rid of hazardous substances and to increase its yield of bioactive compounds [67,68]. Although water may be a cheap solvent, propolis has poor solubility in water. Therefore, propolis water extracts are 10-fold lower in their phenolic contents than ethanol extracts. In addition, they retain the strong flavor and aroma of propolis [68]. Moreover, propolis contains allergenic components: caffeic acids derivates (e.g., 3-methyl-2-butenyl caffeate and phenylethyl caffeate), as well as benzyl salicylate and benzyl cinnamate [80]. Therefore, propolis use/consumption should be contraindicated in individuals with known allergies.\n\n2.3. Bee Pollen: Its Constituents, Biological, and Pharmacological Activities\nBee pollen is an api-material that originally comprises male gametophytes or spermatophytes of flowers, which stick to bee body. Bee workers mix these floral pollens with honey, nectar, and bee saliva. The latter is rich in various enzymes e.g., amylase, catalase, as well as lactic acid bacteria, which cause pollen fermentation [36,83,84]. Hence, the tiny wind pollen grains collected by bees aggregate together to form granules or pellets of 1.4–4 mm in size [84].\nIn addition to water, which in order constitutes 20–30% and 6–8% of the content of recently collected and dried bee pollen, bee pollen contains around 200 chemical compounds. Like other bee products, its composition varies considerably according to botanical origin. Carbohydrates account for the most abundant ingredient (18.50–84.25%), and reducing sugars such as glucose, fructose, and sucrose constitute the vastest majority (13–55%). Other major elements include proteins and essential amino acids (5–60%), unsaturated and saturated fatty acids (0.15–31.26%), crude fiber (0.3–20%), nucleic acids (especially RNA), and various minerals (e.g., potassium, phosphorus, calcium, magnesium, zinc, copper, manganese, and iron) [36,83,84,85,86]. In addition, its average total phenolic content is 30.59 mg gallic acid equivalents (GAE)/g, but again it varies considerably based on floral origin (0.69–213.20 mg GAE/g) [86]. Moreover, bee pollen is abundant in both water- and fat-soluble vitamins e.g., β-carotene (vitamin A precursor), ascorbic acid (C), tocopherol (E), folic acid (B9), and other vitamin B, especially niacin. Bee pollen contains other elements that still need to be explored (2–5%) [83]. Therefore, bee pollen represents a perfect whole health-promoting food. In fact, comparisons of the percentages of nutrients in bee pollen with daily required intake of an adult individual revealed that few grams of bee pollen can meet daily human nutritional requirements [83,84].\nBee pollen demonstrates various biological properties and therapeutic activities e.g., antioxidant, anti-inflammatory, anti-lipidemic, anticancer, antiallergic, and antimicrobial [36,87]. Existing knowledge emphasizes its antiaging effects: it reduced the production of age-related pigment known as lipofuscin (induced by oral peroxidized corn oil or intravenous alloxan injection) in cardiac muscle, brain, liver, and suprarenal gland in aged mice (reviewed in [34]).\nThe composition of bee pollens depends primarily on its botanical source since nutrient contents (e.g., polyphenols) of pollen grains, which support their survival and fusion with female gametes, vary between different plants [83,84]. Storage conditions are of great importance were it to retain its biological activities. Bee pollen should be consumed fresh soon after collection. Most of its major elements (reducing sugars, total proteins, vitamin C, and provitamin A) are destroyed at 40 °C. Lyophilization damages its vitamin content while freezing is recommended for the storage of bee pollen since it does not affect its chemical structure [83].\nDry pollen pellets resist decay due to their tough outer coat, which comprises two layers made of cellulose and sporopollenin [88,89]. However, ingestion of bee pollen by humans may not yield its optimal nutritional value because the hard sporopollenin shell hinders access of digestive secretions to the nutrient-rich core of the pellet. Biological, chemical, and mechanical techniques are used to break bee pollen microcapsules in order to enhance its digestibility in the gut. However, these methods may be expensive or ineffective i.e., they degrade important nutrients via enzymatic activity [88,90]. Ultraviolet spectroscopy and high performance liquid chromatography-photo diode array show that processing bee pollen through the use of an edible lipid-surfactant mixture (Captex 355 and Tween 80) increases its yield of polyphenols and flavonoid aglycones [90].\n\n2.4. Safety Profile of Royal Jelly, Propolis, and Bee Pollen\nPropolis exists in a plethora of commercial products that are directly consumed or used by humans e.g., lozenges, soap, toothpastes and mouth wash, creams, gels, cough syrups, wines, cakes, chewing gums, candies, shampoo, chocolate, skin lotions, processed meat, etc. [67]. In addition, royal jelly, bee pollen, and propolis are widely used as dietary supplements in many parts of the world [36,37,38,39]. Existing knowledge denotes no adverse effects from their consumption either in rodents or in humans [39,66]. The safety of pinocembrin, a flavonoid available in propolis and an approved drug in China, is documented since its elimination from the body is rapid [91]. The safety profile of bee pollen (both crude and processed) has been empirically tested. Oral consumption of bee pollen (up to 2 g/kg body weight) expressed no allergic reactions in mice including behavioral changes, salivation, diarrhea, respiratory or autonomic responses, restlessness, convulsions, tremors, or death [90]. In fact, the German Federal Board of Health acknowledges bee pollen as an official medicine [36].\nSeveral lines of evidence support the anti-allergic effect of propolis and royal jelly. This effect involves inhibiting mast cell degranulation, suppressing cysteinyl-leukotriene release, as well as reducing serum histamine, IgG, and IgE levels in various allergic conditions by suppressing histamine H1 receptor [37,39,92]. Nevertheless, rare allergic reactions to bee products other than bee venom are documented in the literature. They are most frequent in small children [80,93]. Examples of such reactions comprise contact dermatitis in beekeepers following the handling of propolis, as well as contact stomatitis and oral mucositis after the usage of lozenges containing propolis [80]. Hence, bee products should be used with caution, especially in people with known allergies, pregnant and lactating women, and small children [61]. In addition, bee products can be safely consumed after adequate processing. Processing involves removal of known allergens such as enzyme treatment of royal jelly and filtration of bee venom by stepped-gradient open column [2,94]."}

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Apitherapy as a Possible Complementary Treatment for Sarcopenia\nRock paintings from the Stone Age portray consumption of bee products by humans [27]. The first evidence of human usage of bee products for therapeutic and cosmetic purposes dates back 6000 years in ancient Egypt and later in China, Greece, and Rome [27,28,29,30]. Current research interest is directed toward the use of natural substances, including bee products, as potential pharmaceuticals to modify disease progression [31]. The term “apitherapy” describes a category of complementary and alternative medicine that comprises therapeutic use of various bee products including apilarnil (atomized drone larva) to prevent and treat illnesses [30].\nBee workers of either Apis mellifera or Apis cerana species—the former is common in Europe, Asia, Africa, and America while the latter exists only in southern and southeastern Asia—produce and store multiple bioactive substances [32]. Royal jelly, propolis, bee pollen, honey, bee venom, bee bread, and bee wax are common products of the bee hive. They all (to a varying degree) possess multiple health promoting properties due to their high content of natural antioxidants such as flavonoids, phenols, or terpenoids [28,32]. Research documents variability in contents and effects of every single bee product, mainly due to the influence of bee species, botanical origin, geographic location, season, extraction, and handling procedures [2,28].\nSeveral lines of evidence describe anti-aging effects of royal jelly, bee pollen, and propolis both in humans and laboratory animals [2,33,34,35]. These three products are widely used as dietary supplements [36,37,38,39]. In the meantime, the literature gives examples of numerous dietary supplements that could successfully prevent or alleviate the progression of muscle mass loss in old age [40,41,42]. Bee products represent a part of this interventional strategy. However, the extent to which bee products can affect sarcopenia as well as understanding of their underlying mechanism of action are far from being clear. Therefore, we conducted this review with the aim of investigating the anti-aging properties of these products with a focus on skeletal muscle functioning in advanced age. In this respect, we reviewed animal and human studies investigating effects of the aforementioned products on skeletal muscle aging and elaborated on different mechanisms underlying these effects. Studies included in this review were retrieved by searching PubMed and Google scholar using a combination of terminologies of “sarcopenia, muscle wasting, muscle mass, lean body mass, skeletal muscle, motor” with “royal jelly, honey, bee pollen, propolis, bee venom, bee bread, bee wax, chrysin, apamin, caffeic acid phenethyl ester”. Snow ball manual search using reference lists of retrieved studies was also conducted. This search resulted in a number of studies, which addressed muscle wasting and related dynamics through the use of three bee products, namely royal jelly, bee pollen, and propolis. Figure 1, Panel A and Panel B, summarizes the chemical composition and biological properties of these bee products while this section elaborates on these products in depth.\n\n2.1. Royal Jelly: Its Constituents, Biological, and Pharmacological Activities\nRoyal jelly is a thick, milky, white-yellowish, acidic colloid substance secreted from the hypopharyngeal and mandibular salivary glands of young nurse honey bees (5–15 days old) [32,43]. In general, fresh royal jelly mostly consists of water (67% w/w) in addition to carbohydrates (16%), proteins and amino acids (12.5%), fat (5%), and many other elements [32]. However, royal jelly content of these substances noticeably varies depending on numerous factors like botanical source, bee species, bee artificial feeding, weather, season, location, method of processing, and the like [2,44].\nProtein is the most copious active element in royal jelly, representing half the weight of its dry matter [2]. It vastly comprises nine 49–87 kDa water-insoluble proteins, known as major royal jelly proteins 1–9 (MRJPs1-9) [2,45]. MRJPs constitute more than 80% of royal jelly protein content, and MRJPs1–5 constitute 82–90% of all MRJPs. MRJPs contain 400–578 amino acids that contribute to the antioxidant effect of royal jelly as well as its role in cell proliferation, cell adhesion, cell growth, and immunity [46,47]. Novel non-MRJPs proteins have been newly discovered [48]. Royalisin, jelleines, and aspimin are examples of other proteins that exist in royal jelly, albeit in small amounts. These proteins as well as MRJPs demonstrate strong antimicrobial and bactericidal activities even against the most drug-resistant bacterial strains such as methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, vancomycin-resistant Enterococci, as well as extended-spectrum β-lactamase-producing Proteus mirabilis and Escherichia coli [28,29].\nCarbohydrates (e.g., fructose, glucose maltose, trehalose, melibiose, ribose, and erlose) constitute 7.5–16% or royal jelly content [49]. Reducing sugars in royal jelly are thought to contribute to its epigenetic effect through the activation of insulin-like growth factor 1 (IGF-1) and mammalian target of rapamycin (mTOR) signaling cascades. Thus, they stimulate caste differentiation of Apis mellifera larvae into queens by increasing intake of food and key nutrients [50].\nLipids make up 7–18% of the dry weight of royal jelly. This fraction largely comprises a group of unique and rare saturated or monounsaturated short and medium chain fatty acids that are terminally or internally hydroxylated with terminal mono- or dicarboxylic acid functions [2,28]. The vast majority of royal jelly fat content (80–85%) consists of short hydroxyl fatty acids such as trans-10-hydroxy-2-decenoic acid (10-HDA), which exists only in royal jelly; and therefore, it is known as royal jelly acid or queen bee acid [28,49,51]. 10-HDA is one of the most potent bioactive elements in royal jelly expressing strong anti-aging, neuroprotective, antiproliferative, antimicrobial, antioxidant, anti-inflammatory, and epigenetic effects [52,53,54,55,56,57,58]. In addition, the lipid fraction of royal jelly contains phenolic acids (4–10%), wax (5–6%), steroids (3–4%), and phospholipids (0.4–0.8%) [49].\nA wide range of minor constituents and bioactive compounds exist profusely in royal jelly such as acetylcholine, nucleotides (adenosine, guanosine, adenosine tri-phosphate (ATP), adenosine monophosphate (AMP)), minerals (iron, sodium, calcium, potassium, zinc, magnesium, manganese, and copper), amino acids (8 out of 9 essential amino acids Val, Leu, Ile, Thr, Met, Phe, Lys, and Trp), vitamins (retinol (A), ascorbic acid (C), tocopherol (E), riboflavin (B2), niacin (B3), and other B vitamins), esters, aldehydes, ketones, alcohol, and minor heterocyclic compounds [2,28,49,59,60,61]. It is worth noting that royal jelly loses most of its bioactive ingredients and biological properties when stored at a temperature of 5 °C or higher. Therefore, freezing is the best method to store royal jelly [62]. Enzymatic treatment of royal jelly removes allergen proteins and enhances its nutrient content in addition to improving its digestibility and absorption in the gut without altering its freshness [2,59].\nRoyal jelly has been historically used as a beautifying agent by famous queens such as Cleopatra, and it is still involved in the cosmetic industry [29,56]. Its rich content of bioactive compounds grants it a plethora of diverse health benefits such as antioxidant, anti-inflammatory, neurotrophic, hypotensive, antidiabetic, antilipidemic, antirheumatic, anticarcinogenic, anti-fatigue, antiadipogenic, and antimicrobial activities [43,45,63]. Therefore, it is widely used to treat multiple serious conditions including diabetes, hypertension, hyperlipidemia, cancer, skin diseases, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease [2,43,46,59,64]. In addition, bee queens (which enjoy long lifespan as well as super fertility and physical qualities) consume royal jelly throughout their entire lives, and royal jelly is considered a promising anti-aging nutraceutical that can positively enhance fertility and improve body composition [2].\n\n2.2. Propolis: Its Constituents, Biological, and Pharmacological Activities\nPropolis, also known as bee glue, is a sticky wax-like substance that constitutes a mixture of bee salivary secretions, bee wax, and resinous sap occurring in the bark and leaf-buds of specific plants [37,65]. It comes in green, red, brown, or black colors based on the collected local flora [66]. The word propolis comprises two Greek words “pro” and “polis”, which in order mean “in front of or at the entrance to” and “community or city”. Propolis is a hive-defensive substance, which bees use to protect and repair their hives [67].\nPropolis is a unique product of a complex composition that comprises more than 420 chemical substances [37,68]. Nonetheless, its composition and biological activities vary considerably depending on its botanical and geographical origins as well as the time of harvesting [38,65,67]. Propolis is rich in oxyprenylated phenylpropanoids—secondary metabolites from plants, fungi, and bacteria [69]—such as 7-isopentenyloxucoumarin, boropinic acid, 4-geranyloxyferulic acid, and auraptene. The last two exist in raw Italian propolis at high concentrations: 107.12 and 145.37 μg/g of dry propolis, respectively. Flavonoids, a large group of phenolic compounds, are abundant in Italian propolis, and they are differentiated into several groups including flavanones (e.g., naringenine, 4.4 mg/g), flavones (e.g., apigenine, 1.7 mg/g), flavonols (e.g., galaning, 0.9 mg/g), tannins (e.g., gallic acid 8.4 mg/g), catechins (expressed as (+)-catechin 0.4 mg/g, and caffeic acid and its esters (expressed as caffeic acid, 9.2 mg/g) [69]. The most profuse flavonoids in ethanolic extracts of Brazilian propolis are artepillin C (38.6 mg/g), coumaric acid (10.6 mg/g), and kaempferide (12.6 mg/g) [70]. Key other constituents of propolis include polyphenol (e.g., phenolic acids and aromatic esters), phenolic aldehydes, terpenoids, ketones, enzymes (e.g., α- and β-amylase), vitamins (e.g., thiamin (B1), riboflavin (B2), pyridoxine (B6), ascorbic acid (C), tocopherol (E)), minerals (e.g., calcium, potassium, magnesium, iron, sodium, barium) essential oils, alcohol, fatty acids, β-steroids, and many other elements [37,38,67,68,71].\nThe attention of several drug targeting studies has recently been focused on the therapeutic activities of individual bioactive compounds in propolis [65,68]. Flavonoids comprise the majority of mostly studies bioactive substances in propolis. Chrysin (5,7-dihydroxyflavone) is a flavonoid that exists in certain mushrooms, flowers (e.g., blue passion flower), and in other bee products (e.g., honey). It expresses anti-inflammatory, antioxidant, anti-proliferative, and neuroprotective effects [72]. Caffeic acid phenethyl ester (CAPE), a derivative of hydroxycinnamic acid, expresses anti-oxidant, immunomodulatory, anti-inflammatory, antiviral, and ant-neoplastic properties [73,74,75]. Pinocembrin (5,7-dihydroxyflavanone) is the most copious flavonoid in propolis—1 g of balsam/an ethanolic extract from poplar propolis found in Spain contains up to 606–701 mg of pinocembrin [76]. It exists in numerous plants (e.g., Eucalyptus and Populus). It exhibits anti-inflammatory, antioxidant, antimicrobial, and antiproliferative activities [77,78].\nEssential/volatile oils are major bioactive constituents of propolis, and they contribute to its special aroma [79,80]. They also, partially, contribute to the strong antimicrobial, antioxidant, and anticancer activities of propolis [79,81,82]. The volatile fraction of propolis varies in each sample even within a single country due to plant source and climate [79]. For instance, cumulative knowledge shows that volatile oils in propolis found in countries surrounding the Mediterranean depend mainly on the botanical origin. They primarily comprise poplar-derived compounds (e.g., benzoic acid and its esters and oxygenated sesquiterpene β-eudesmol) and conifer-derived compounds such as the hydrocarbon monoterpene α-pinene [80]. Interestingly, the number of volatile compounds derived from a single type of propolis is also reported to vary according to extraction techniques. In this regard, reports from China show that traditional hydrodistillation, steam-distillation extraction, and dynamic headspace sampling could characterize around 12, 40 and 70 type of volatile components of propolis, respectively [79]. Moreover, the level of antimicrobial activity of volatile compounds of propolis greatly depends on their extent of purification [82].\nThanks to its countless bioactive elements, propolis enjoys a range of versatile biological and pharmacological properties including antimicrobial, antiviral, antifungal, antioxidant, anti-inflammatory, antineoplastic, antiaging, and cytostatic properties. In addition, it is considered a perfect natural food preservative due to its antimicrobial activity [35,38,65,66,68,71]. Because of its enormous health-promoting activities, propolis is widely used as a dietary supplement in many countries, especially in Japan [37,38,39].\nPropolis is not suitable for use in its crude state since it may contact harmful materials e.g., asphalt from the road [68]. Using solvents like ethanol, glycerol, chloroform, ether and acetone or water is necessary to get rid of hazardous substances and to increase its yield of bioactive compounds [67,68]. Although water may be a cheap solvent, propolis has poor solubility in water. Therefore, propolis water extracts are 10-fold lower in their phenolic contents than ethanol extracts. In addition, they retain the strong flavor and aroma of propolis [68]. Moreover, propolis contains allergenic components: caffeic acids derivates (e.g., 3-methyl-2-butenyl caffeate and phenylethyl caffeate), as well as benzyl salicylate and benzyl cinnamate [80]. Therefore, propolis use/consumption should be contraindicated in individuals with known allergies.\n\n2.3. Bee Pollen: Its Constituents, Biological, and Pharmacological Activities\nBee pollen is an api-material that originally comprises male gametophytes or spermatophytes of flowers, which stick to bee body. Bee workers mix these floral pollens with honey, nectar, and bee saliva. The latter is rich in various enzymes e.g., amylase, catalase, as well as lactic acid bacteria, which cause pollen fermentation [36,83,84]. Hence, the tiny wind pollen grains collected by bees aggregate together to form granules or pellets of 1.4–4 mm in size [84].\nIn addition to water, which in order constitutes 20–30% and 6–8% of the content of recently collected and dried bee pollen, bee pollen contains around 200 chemical compounds. Like other bee products, its composition varies considerably according to botanical origin. Carbohydrates account for the most abundant ingredient (18.50–84.25%), and reducing sugars such as glucose, fructose, and sucrose constitute the vastest majority (13–55%). Other major elements include proteins and essential amino acids (5–60%), unsaturated and saturated fatty acids (0.15–31.26%), crude fiber (0.3–20%), nucleic acids (especially RNA), and various minerals (e.g., potassium, phosphorus, calcium, magnesium, zinc, copper, manganese, and iron) [36,83,84,85,86]. In addition, its average total phenolic content is 30.59 mg gallic acid equivalents (GAE)/g, but again it varies considerably based on floral origin (0.69–213.20 mg GAE/g) [86]. Moreover, bee pollen is abundant in both water- and fat-soluble vitamins e.g., β-carotene (vitamin A precursor), ascorbic acid (C), tocopherol (E), folic acid (B9), and other vitamin B, especially niacin. Bee pollen contains other elements that still need to be explored (2–5%) [83]. Therefore, bee pollen represents a perfect whole health-promoting food. In fact, comparisons of the percentages of nutrients in bee pollen with daily required intake of an adult individual revealed that few grams of bee pollen can meet daily human nutritional requirements [83,84].\nBee pollen demonstrates various biological properties and therapeutic activities e.g., antioxidant, anti-inflammatory, anti-lipidemic, anticancer, antiallergic, and antimicrobial [36,87]. Existing knowledge emphasizes its antiaging effects: it reduced the production of age-related pigment known as lipofuscin (induced by oral peroxidized corn oil or intravenous alloxan injection) in cardiac muscle, brain, liver, and suprarenal gland in aged mice (reviewed in [34]).\nThe composition of bee pollens depends primarily on its botanical source since nutrient contents (e.g., polyphenols) of pollen grains, which support their survival and fusion with female gametes, vary between different plants [83,84]. Storage conditions are of great importance were it to retain its biological activities. Bee pollen should be consumed fresh soon after collection. Most of its major elements (reducing sugars, total proteins, vitamin C, and provitamin A) are destroyed at 40 °C. Lyophilization damages its vitamin content while freezing is recommended for the storage of bee pollen since it does not affect its chemical structure [83].\nDry pollen pellets resist decay due to their tough outer coat, which comprises two layers made of cellulose and sporopollenin [88,89]. However, ingestion of bee pollen by humans may not yield its optimal nutritional value because the hard sporopollenin shell hinders access of digestive secretions to the nutrient-rich core of the pellet. Biological, chemical, and mechanical techniques are used to break bee pollen microcapsules in order to enhance its digestibility in the gut. However, these methods may be expensive or ineffective i.e., they degrade important nutrients via enzymatic activity [88,90]. Ultraviolet spectroscopy and high performance liquid chromatography-photo diode array show that processing bee pollen through the use of an edible lipid-surfactant mixture (Captex 355 and Tween 80) increases its yield of polyphenols and flavonoid aglycones [90].\n\n2.4. Safety Profile of Royal Jelly, Propolis, and Bee Pollen\nPropolis exists in a plethora of commercial products that are directly consumed or used by humans e.g., lozenges, soap, toothpastes and mouth wash, creams, gels, cough syrups, wines, cakes, chewing gums, candies, shampoo, chocolate, skin lotions, processed meat, etc. [67]. In addition, royal jelly, bee pollen, and propolis are widely used as dietary supplements in many parts of the world [36,37,38,39]. Existing knowledge denotes no adverse effects from their consumption either in rodents or in humans [39,66]. The safety of pinocembrin, a flavonoid available in propolis and an approved drug in China, is documented since its elimination from the body is rapid [91]. The safety profile of bee pollen (both crude and processed) has been empirically tested. Oral consumption of bee pollen (up to 2 g/kg body weight) expressed no allergic reactions in mice including behavioral changes, salivation, diarrhea, respiratory or autonomic responses, restlessness, convulsions, tremors, or death [90]. In fact, the German Federal Board of Health acknowledges bee pollen as an official medicine [36].\nSeveral lines of evidence support the anti-allergic effect of propolis and royal jelly. This effect involves inhibiting mast cell degranulation, suppressing cysteinyl-leukotriene release, as well as reducing serum histamine, IgG, and IgE levels in various allergic conditions by suppressing histamine H1 receptor [37,39,92]. Nevertheless, rare allergic reactions to bee products other than bee venom are documented in the literature. They are most frequent in small children [80,93]. Examples of such reactions comprise contact dermatitis in beekeepers following the handling of propolis, as well as contact stomatitis and oral mucositis after the usage of lozenges containing propolis [80]. Hence, bee products should be used with caution, especially in people with known allergies, pregnant and lactating women, and small children [61]. In addition, bee products can be safely consumed after adequate processing. Processing involves removal of known allergens such as enzyme treatment of royal jelly and filtration of bee venom by stepped-gradient open column [2,94]."}

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Apitherapy as a Possible Complementary Treatment for Sarcopenia\nRock paintings from the Stone Age portray consumption of bee products by humans [27]. The first evidence of human usage of bee products for therapeutic and cosmetic purposes dates back 6000 years in ancient Egypt and later in China, Greece, and Rome [27,28,29,30]. Current research interest is directed toward the use of natural substances, including bee products, as potential pharmaceuticals to modify disease progression [31]. The term “apitherapy” describes a category of complementary and alternative medicine that comprises therapeutic use of various bee products including apilarnil (atomized drone larva) to prevent and treat illnesses [30].\nBee workers of either Apis mellifera or Apis cerana species—the former is common in Europe, Asia, Africa, and America while the latter exists only in southern and southeastern Asia—produce and store multiple bioactive substances [32]. Royal jelly, propolis, bee pollen, honey, bee venom, bee bread, and bee wax are common products of the bee hive. They all (to a varying degree) possess multiple health promoting properties due to their high content of natural antioxidants such as flavonoids, phenols, or terpenoids [28,32]. Research documents variability in contents and effects of every single bee product, mainly due to the influence of bee species, botanical origin, geographic location, season, extraction, and handling procedures [2,28].\nSeveral lines of evidence describe anti-aging effects of royal jelly, bee pollen, and propolis both in humans and laboratory animals [2,33,34,35]. These three products are widely used as dietary supplements [36,37,38,39]. In the meantime, the literature gives examples of numerous dietary supplements that could successfully prevent or alleviate the progression of muscle mass loss in old age [40,41,42]. Bee products represent a part of this interventional strategy. However, the extent to which bee products can affect sarcopenia as well as understanding of their underlying mechanism of action are far from being clear. Therefore, we conducted this review with the aim of investigating the anti-aging properties of these products with a focus on skeletal muscle functioning in advanced age. In this respect, we reviewed animal and human studies investigating effects of the aforementioned products on skeletal muscle aging and elaborated on different mechanisms underlying these effects. Studies included in this review were retrieved by searching PubMed and Google scholar using a combination of terminologies of “sarcopenia, muscle wasting, muscle mass, lean body mass, skeletal muscle, motor” with “royal jelly, honey, bee pollen, propolis, bee venom, bee bread, bee wax, chrysin, apamin, caffeic acid phenethyl ester”. Snow ball manual search using reference lists of retrieved studies was also conducted. This search resulted in a number of studies, which addressed muscle wasting and related dynamics through the use of three bee products, namely royal jelly, bee pollen, and propolis. Figure 1, Panel A and Panel B, summarizes the chemical composition and biological properties of these bee products while this section elaborates on these products in depth.\n\n2.1. Royal Jelly: Its Constituents, Biological, and Pharmacological Activities\nRoyal jelly is a thick, milky, white-yellowish, acidic colloid substance secreted from the hypopharyngeal and mandibular salivary glands of young nurse honey bees (5–15 days old) [32,43]. In general, fresh royal jelly mostly consists of water (67% w/w) in addition to carbohydrates (16%), proteins and amino acids (12.5%), fat (5%), and many other elements [32]. However, royal jelly content of these substances noticeably varies depending on numerous factors like botanical source, bee species, bee artificial feeding, weather, season, location, method of processing, and the like [2,44].\nProtein is the most copious active element in royal jelly, representing half the weight of its dry matter [2]. It vastly comprises nine 49–87 kDa water-insoluble proteins, known as major royal jelly proteins 1–9 (MRJPs1-9) [2,45]. MRJPs constitute more than 80% of royal jelly protein content, and MRJPs1–5 constitute 82–90% of all MRJPs. MRJPs contain 400–578 amino acids that contribute to the antioxidant effect of royal jelly as well as its role in cell proliferation, cell adhesion, cell growth, and immunity [46,47]. Novel non-MRJPs proteins have been newly discovered [48]. Royalisin, jelleines, and aspimin are examples of other proteins that exist in royal jelly, albeit in small amounts. These proteins as well as MRJPs demonstrate strong antimicrobial and bactericidal activities even against the most drug-resistant bacterial strains such as methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, vancomycin-resistant Enterococci, as well as extended-spectrum β-lactamase-producing Proteus mirabilis and Escherichia coli [28,29].\nCarbohydrates (e.g., fructose, glucose maltose, trehalose, melibiose, ribose, and erlose) constitute 7.5–16% or royal jelly content [49]. Reducing sugars in royal jelly are thought to contribute to its epigenetic effect through the activation of insulin-like growth factor 1 (IGF-1) and mammalian target of rapamycin (mTOR) signaling cascades. Thus, they stimulate caste differentiation of Apis mellifera larvae into queens by increasing intake of food and key nutrients [50].\nLipids make up 7–18% of the dry weight of royal jelly. This fraction largely comprises a group of unique and rare saturated or monounsaturated short and medium chain fatty acids that are terminally or internally hydroxylated with terminal mono- or dicarboxylic acid functions [2,28]. The vast majority of royal jelly fat content (80–85%) consists of short hydroxyl fatty acids such as trans-10-hydroxy-2-decenoic acid (10-HDA), which exists only in royal jelly; and therefore, it is known as royal jelly acid or queen bee acid [28,49,51]. 10-HDA is one of the most potent bioactive elements in royal jelly expressing strong anti-aging, neuroprotective, antiproliferative, antimicrobial, antioxidant, anti-inflammatory, and epigenetic effects [52,53,54,55,56,57,58]. In addition, the lipid fraction of royal jelly contains phenolic acids (4–10%), wax (5–6%), steroids (3–4%), and phospholipids (0.4–0.8%) [49].\nA wide range of minor constituents and bioactive compounds exist profusely in royal jelly such as acetylcholine, nucleotides (adenosine, guanosine, adenosine tri-phosphate (ATP), adenosine monophosphate (AMP)), minerals (iron, sodium, calcium, potassium, zinc, magnesium, manganese, and copper), amino acids (8 out of 9 essential amino acids Val, Leu, Ile, Thr, Met, Phe, Lys, and Trp), vitamins (retinol (A), ascorbic acid (C), tocopherol (E), riboflavin (B2), niacin (B3), and other B vitamins), esters, aldehydes, ketones, alcohol, and minor heterocyclic compounds [2,28,49,59,60,61]. It is worth noting that royal jelly loses most of its bioactive ingredients and biological properties when stored at a temperature of 5 °C or higher. Therefore, freezing is the best method to store royal jelly [62]. Enzymatic treatment of royal jelly removes allergen proteins and enhances its nutrient content in addition to improving its digestibility and absorption in the gut without altering its freshness [2,59].\nRoyal jelly has been historically used as a beautifying agent by famous queens such as Cleopatra, and it is still involved in the cosmetic industry [29,56]. Its rich content of bioactive compounds grants it a plethora of diverse health benefits such as antioxidant, anti-inflammatory, neurotrophic, hypotensive, antidiabetic, antilipidemic, antirheumatic, anticarcinogenic, anti-fatigue, antiadipogenic, and antimicrobial activities [43,45,63]. Therefore, it is widely used to treat multiple serious conditions including diabetes, hypertension, hyperlipidemia, cancer, skin diseases, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease [2,43,46,59,64]. In addition, bee queens (which enjoy long lifespan as well as super fertility and physical qualities) consume royal jelly throughout their entire lives, and royal jelly is considered a promising anti-aging nutraceutical that can positively enhance fertility and improve body composition [2].\n\n2.2. Propolis: Its Constituents, Biological, and Pharmacological Activities\nPropolis, also known as bee glue, is a sticky wax-like substance that constitutes a mixture of bee salivary secretions, bee wax, and resinous sap occurring in the bark and leaf-buds of specific plants [37,65]. It comes in green, red, brown, or black colors based on the collected local flora [66]. The word propolis comprises two Greek words “pro” and “polis”, which in order mean “in front of or at the entrance to” and “community or city”. Propolis is a hive-defensive substance, which bees use to protect and repair their hives [67].\nPropolis is a unique product of a complex composition that comprises more than 420 chemical substances [37,68]. Nonetheless, its composition and biological activities vary considerably depending on its botanical and geographical origins as well as the time of harvesting [38,65,67]. Propolis is rich in oxyprenylated phenylpropanoids—secondary metabolites from plants, fungi, and bacteria [69]—such as 7-isopentenyloxucoumarin, boropinic acid, 4-geranyloxyferulic acid, and auraptene. The last two exist in raw Italian propolis at high concentrations: 107.12 and 145.37 μg/g of dry propolis, respectively. Flavonoids, a large group of phenolic compounds, are abundant in Italian propolis, and they are differentiated into several groups including flavanones (e.g., naringenine, 4.4 mg/g), flavones (e.g., apigenine, 1.7 mg/g), flavonols (e.g., galaning, 0.9 mg/g), tannins (e.g., gallic acid 8.4 mg/g), catechins (expressed as (+)-catechin 0.4 mg/g, and caffeic acid and its esters (expressed as caffeic acid, 9.2 mg/g) [69]. The most profuse flavonoids in ethanolic extracts of Brazilian propolis are artepillin C (38.6 mg/g), coumaric acid (10.6 mg/g), and kaempferide (12.6 mg/g) [70]. Key other constituents of propolis include polyphenol (e.g., phenolic acids and aromatic esters), phenolic aldehydes, terpenoids, ketones, enzymes (e.g., α- and β-amylase), vitamins (e.g., thiamin (B1), riboflavin (B2), pyridoxine (B6), ascorbic acid (C), tocopherol (E)), minerals (e.g., calcium, potassium, magnesium, iron, sodium, barium) essential oils, alcohol, fatty acids, β-steroids, and many other elements [37,38,67,68,71].\nThe attention of several drug targeting studies has recently been focused on the therapeutic activities of individual bioactive compounds in propolis [65,68]. Flavonoids comprise the majority of mostly studies bioactive substances in propolis. Chrysin (5,7-dihydroxyflavone) is a flavonoid that exists in certain mushrooms, flowers (e.g., blue passion flower), and in other bee products (e.g., honey). It expresses anti-inflammatory, antioxidant, anti-proliferative, and neuroprotective effects [72]. Caffeic acid phenethyl ester (CAPE), a derivative of hydroxycinnamic acid, expresses anti-oxidant, immunomodulatory, anti-inflammatory, antiviral, and ant-neoplastic properties [73,74,75]. Pinocembrin (5,7-dihydroxyflavanone) is the most copious flavonoid in propolis—1 g of balsam/an ethanolic extract from poplar propolis found in Spain contains up to 606–701 mg of pinocembrin [76]. It exists in numerous plants (e.g., Eucalyptus and Populus). It exhibits anti-inflammatory, antioxidant, antimicrobial, and antiproliferative activities [77,78].\nEssential/volatile oils are major bioactive constituents of propolis, and they contribute to its special aroma [79,80]. They also, partially, contribute to the strong antimicrobial, antioxidant, and anticancer activities of propolis [79,81,82]. The volatile fraction of propolis varies in each sample even within a single country due to plant source and climate [79]. For instance, cumulative knowledge shows that volatile oils in propolis found in countries surrounding the Mediterranean depend mainly on the botanical origin. They primarily comprise poplar-derived compounds (e.g., benzoic acid and its esters and oxygenated sesquiterpene β-eudesmol) and conifer-derived compounds such as the hydrocarbon monoterpene α-pinene [80]. Interestingly, the number of volatile compounds derived from a single type of propolis is also reported to vary according to extraction techniques. In this regard, reports from China show that traditional hydrodistillation, steam-distillation extraction, and dynamic headspace sampling could characterize around 12, 40 and 70 type of volatile components of propolis, respectively [79]. Moreover, the level of antimicrobial activity of volatile compounds of propolis greatly depends on their extent of purification [82].\nThanks to its countless bioactive elements, propolis enjoys a range of versatile biological and pharmacological properties including antimicrobial, antiviral, antifungal, antioxidant, anti-inflammatory, antineoplastic, antiaging, and cytostatic properties. In addition, it is considered a perfect natural food preservative due to its antimicrobial activity [35,38,65,66,68,71]. Because of its enormous health-promoting activities, propolis is widely used as a dietary supplement in many countries, especially in Japan [37,38,39].\nPropolis is not suitable for use in its crude state since it may contact harmful materials e.g., asphalt from the road [68]. Using solvents like ethanol, glycerol, chloroform, ether and acetone or water is necessary to get rid of hazardous substances and to increase its yield of bioactive compounds [67,68]. Although water may be a cheap solvent, propolis has poor solubility in water. Therefore, propolis water extracts are 10-fold lower in their phenolic contents than ethanol extracts. In addition, they retain the strong flavor and aroma of propolis [68]. Moreover, propolis contains allergenic components: caffeic acids derivates (e.g., 3-methyl-2-butenyl caffeate and phenylethyl caffeate), as well as benzyl salicylate and benzyl cinnamate [80]. Therefore, propolis use/consumption should be contraindicated in individuals with known allergies.\n\n2.3. Bee Pollen: Its Constituents, Biological, and Pharmacological Activities\nBee pollen is an api-material that originally comprises male gametophytes or spermatophytes of flowers, which stick to bee body. Bee workers mix these floral pollens with honey, nectar, and bee saliva. The latter is rich in various enzymes e.g., amylase, catalase, as well as lactic acid bacteria, which cause pollen fermentation [36,83,84]. Hence, the tiny wind pollen grains collected by bees aggregate together to form granules or pellets of 1.4–4 mm in size [84].\nIn addition to water, which in order constitutes 20–30% and 6–8% of the content of recently collected and dried bee pollen, bee pollen contains around 200 chemical compounds. Like other bee products, its composition varies considerably according to botanical origin. Carbohydrates account for the most abundant ingredient (18.50–84.25%), and reducing sugars such as glucose, fructose, and sucrose constitute the vastest majority (13–55%). Other major elements include proteins and essential amino acids (5–60%), unsaturated and saturated fatty acids (0.15–31.26%), crude fiber (0.3–20%), nucleic acids (especially RNA), and various minerals (e.g., potassium, phosphorus, calcium, magnesium, zinc, copper, manganese, and iron) [36,83,84,85,86]. In addition, its average total phenolic content is 30.59 mg gallic acid equivalents (GAE)/g, but again it varies considerably based on floral origin (0.69–213.20 mg GAE/g) [86]. Moreover, bee pollen is abundant in both water- and fat-soluble vitamins e.g., β-carotene (vitamin A precursor), ascorbic acid (C), tocopherol (E), folic acid (B9), and other vitamin B, especially niacin. Bee pollen contains other elements that still need to be explored (2–5%) [83]. Therefore, bee pollen represents a perfect whole health-promoting food. In fact, comparisons of the percentages of nutrients in bee pollen with daily required intake of an adult individual revealed that few grams of bee pollen can meet daily human nutritional requirements [83,84].\nBee pollen demonstrates various biological properties and therapeutic activities e.g., antioxidant, anti-inflammatory, anti-lipidemic, anticancer, antiallergic, and antimicrobial [36,87]. Existing knowledge emphasizes its antiaging effects: it reduced the production of age-related pigment known as lipofuscin (induced by oral peroxidized corn oil or intravenous alloxan injection) in cardiac muscle, brain, liver, and suprarenal gland in aged mice (reviewed in [34]).\nThe composition of bee pollens depends primarily on its botanical source since nutrient contents (e.g., polyphenols) of pollen grains, which support their survival and fusion with female gametes, vary between different plants [83,84]. Storage conditions are of great importance were it to retain its biological activities. Bee pollen should be consumed fresh soon after collection. Most of its major elements (reducing sugars, total proteins, vitamin C, and provitamin A) are destroyed at 40 °C. Lyophilization damages its vitamin content while freezing is recommended for the storage of bee pollen since it does not affect its chemical structure [83].\nDry pollen pellets resist decay due to their tough outer coat, which comprises two layers made of cellulose and sporopollenin [88,89]. However, ingestion of bee pollen by humans may not yield its optimal nutritional value because the hard sporopollenin shell hinders access of digestive secretions to the nutrient-rich core of the pellet. Biological, chemical, and mechanical techniques are used to break bee pollen microcapsules in order to enhance its digestibility in the gut. However, these methods may be expensive or ineffective i.e., they degrade important nutrients via enzymatic activity [88,90]. Ultraviolet spectroscopy and high performance liquid chromatography-photo diode array show that processing bee pollen through the use of an edible lipid-surfactant mixture (Captex 355 and Tween 80) increases its yield of polyphenols and flavonoid aglycones [90].\n\n2.4. Safety Profile of Royal Jelly, Propolis, and Bee Pollen\nPropolis exists in a plethora of commercial products that are directly consumed or used by humans e.g., lozenges, soap, toothpastes and mouth wash, creams, gels, cough syrups, wines, cakes, chewing gums, candies, shampoo, chocolate, skin lotions, processed meat, etc. [67]. In addition, royal jelly, bee pollen, and propolis are widely used as dietary supplements in many parts of the world [36,37,38,39]. Existing knowledge denotes no adverse effects from their consumption either in rodents or in humans [39,66]. The safety of pinocembrin, a flavonoid available in propolis and an approved drug in China, is documented since its elimination from the body is rapid [91]. The safety profile of bee pollen (both crude and processed) has been empirically tested. Oral consumption of bee pollen (up to 2 g/kg body weight) expressed no allergic reactions in mice including behavioral changes, salivation, diarrhea, respiratory or autonomic responses, restlessness, convulsions, tremors, or death [90]. In fact, the German Federal Board of Health acknowledges bee pollen as an official medicine [36].\nSeveral lines of evidence support the anti-allergic effect of propolis and royal jelly. This effect involves inhibiting mast cell degranulation, suppressing cysteinyl-leukotriene release, as well as reducing serum histamine, IgG, and IgE levels in various allergic conditions by suppressing histamine H1 receptor [37,39,92]. Nevertheless, rare allergic reactions to bee products other than bee venom are documented in the literature. They are most frequent in small children [80,93]. Examples of such reactions comprise contact dermatitis in beekeepers following the handling of propolis, as well as contact stomatitis and oral mucositis after the usage of lozenges containing propolis [80]. Hence, bee products should be used with caution, especially in people with known allergies, pregnant and lactating women, and small children [61]. In addition, bee products can be safely consumed after adequate processing. Processing involves removal of known allergens such as enzyme treatment of royal jelly and filtration of bee venom by stepped-gradient open column [2,94]."}

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Apitherapy as a Possible Complementary Treatment for Sarcopenia\nRock paintings from the Stone Age portray consumption of bee products by humans [27]. The first evidence of human usage of bee products for therapeutic and cosmetic purposes dates back 6000 years in ancient Egypt and later in China, Greece, and Rome [27,28,29,30]. Current research interest is directed toward the use of natural substances, including bee products, as potential pharmaceuticals to modify disease progression [31]. The term “apitherapy” describes a category of complementary and alternative medicine that comprises therapeutic use of various bee products including apilarnil (atomized drone larva) to prevent and treat illnesses [30].\nBee workers of either Apis mellifera or Apis cerana species—the former is common in Europe, Asia, Africa, and America while the latter exists only in southern and southeastern Asia—produce and store multiple bioactive substances [32]. Royal jelly, propolis, bee pollen, honey, bee venom, bee bread, and bee wax are common products of the bee hive. They all (to a varying degree) possess multiple health promoting properties due to their high content of natural antioxidants such as flavonoids, phenols, or terpenoids [28,32]. Research documents variability in contents and effects of every single bee product, mainly due to the influence of bee species, botanical origin, geographic location, season, extraction, and handling procedures [2,28].\nSeveral lines of evidence describe anti-aging effects of royal jelly, bee pollen, and propolis both in humans and laboratory animals [2,33,34,35]. These three products are widely used as dietary supplements [36,37,38,39]. In the meantime, the literature gives examples of numerous dietary supplements that could successfully prevent or alleviate the progression of muscle mass loss in old age [40,41,42]. Bee products represent a part of this interventional strategy. However, the extent to which bee products can affect sarcopenia as well as understanding of their underlying mechanism of action are far from being clear. Therefore, we conducted this review with the aim of investigating the anti-aging properties of these products with a focus on skeletal muscle functioning in advanced age. In this respect, we reviewed animal and human studies investigating effects of the aforementioned products on skeletal muscle aging and elaborated on different mechanisms underlying these effects. Studies included in this review were retrieved by searching PubMed and Google scholar using a combination of terminologies of “sarcopenia, muscle wasting, muscle mass, lean body mass, skeletal muscle, motor” with “royal jelly, honey, bee pollen, propolis, bee venom, bee bread, bee wax, chrysin, apamin, caffeic acid phenethyl ester”. Snow ball manual search using reference lists of retrieved studies was also conducted. This search resulted in a number of studies, which addressed muscle wasting and related dynamics through the use of three bee products, namely royal jelly, bee pollen, and propolis. Figure 1, Panel A and Panel B, summarizes the chemical composition and biological properties of these bee products while this section elaborates on these products in depth.\n\n2.1. Royal Jelly: Its Constituents, Biological, and Pharmacological Activities\nRoyal jelly is a thick, milky, white-yellowish, acidic colloid substance secreted from the hypopharyngeal and mandibular salivary glands of young nurse honey bees (5–15 days old) [32,43]. In general, fresh royal jelly mostly consists of water (67% w/w) in addition to carbohydrates (16%), proteins and amino acids (12.5%), fat (5%), and many other elements [32]. However, royal jelly content of these substances noticeably varies depending on numerous factors like botanical source, bee species, bee artificial feeding, weather, season, location, method of processing, and the like [2,44].\nProtein is the most copious active element in royal jelly, representing half the weight of its dry matter [2]. It vastly comprises nine 49–87 kDa water-insoluble proteins, known as major royal jelly proteins 1–9 (MRJPs1-9) [2,45]. MRJPs constitute more than 80% of royal jelly protein content, and MRJPs1–5 constitute 82–90% of all MRJPs. MRJPs contain 400–578 amino acids that contribute to the antioxidant effect of royal jelly as well as its role in cell proliferation, cell adhesion, cell growth, and immunity [46,47]. Novel non-MRJPs proteins have been newly discovered [48]. Royalisin, jelleines, and aspimin are examples of other proteins that exist in royal jelly, albeit in small amounts. These proteins as well as MRJPs demonstrate strong antimicrobial and bactericidal activities even against the most drug-resistant bacterial strains such as methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, vancomycin-resistant Enterococci, as well as extended-spectrum β-lactamase-producing Proteus mirabilis and Escherichia coli [28,29].\nCarbohydrates (e.g., fructose, glucose maltose, trehalose, melibiose, ribose, and erlose) constitute 7.5–16% or royal jelly content [49]. Reducing sugars in royal jelly are thought to contribute to its epigenetic effect through the activation of insulin-like growth factor 1 (IGF-1) and mammalian target of rapamycin (mTOR) signaling cascades. Thus, they stimulate caste differentiation of Apis mellifera larvae into queens by increasing intake of food and key nutrients [50].\nLipids make up 7–18% of the dry weight of royal jelly. This fraction largely comprises a group of unique and rare saturated or monounsaturated short and medium chain fatty acids that are terminally or internally hydroxylated with terminal mono- or dicarboxylic acid functions [2,28]. The vast majority of royal jelly fat content (80–85%) consists of short hydroxyl fatty acids such as trans-10-hydroxy-2-decenoic acid (10-HDA), which exists only in royal jelly; and therefore, it is known as royal jelly acid or queen bee acid [28,49,51]. 10-HDA is one of the most potent bioactive elements in royal jelly expressing strong anti-aging, neuroprotective, antiproliferative, antimicrobial, antioxidant, anti-inflammatory, and epigenetic effects [52,53,54,55,56,57,58]. In addition, the lipid fraction of royal jelly contains phenolic acids (4–10%), wax (5–6%), steroids (3–4%), and phospholipids (0.4–0.8%) [49].\nA wide range of minor constituents and bioactive compounds exist profusely in royal jelly such as acetylcholine, nucleotides (adenosine, guanosine, adenosine tri-phosphate (ATP), adenosine monophosphate (AMP)), minerals (iron, sodium, calcium, potassium, zinc, magnesium, manganese, and copper), amino acids (8 out of 9 essential amino acids Val, Leu, Ile, Thr, Met, Phe, Lys, and Trp), vitamins (retinol (A), ascorbic acid (C), tocopherol (E), riboflavin (B2), niacin (B3), and other B vitamins), esters, aldehydes, ketones, alcohol, and minor heterocyclic compounds [2,28,49,59,60,61]. It is worth noting that royal jelly loses most of its bioactive ingredients and biological properties when stored at a temperature of 5 °C or higher. Therefore, freezing is the best method to store royal jelly [62]. Enzymatic treatment of royal jelly removes allergen proteins and enhances its nutrient content in addition to improving its digestibility and absorption in the gut without altering its freshness [2,59].\nRoyal jelly has been historically used as a beautifying agent by famous queens such as Cleopatra, and it is still involved in the cosmetic industry [29,56]. Its rich content of bioactive compounds grants it a plethora of diverse health benefits such as antioxidant, anti-inflammatory, neurotrophic, hypotensive, antidiabetic, antilipidemic, antirheumatic, anticarcinogenic, anti-fatigue, antiadipogenic, and antimicrobial activities [43,45,63]. Therefore, it is widely used to treat multiple serious conditions including diabetes, hypertension, hyperlipidemia, cancer, skin diseases, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease [2,43,46,59,64]. In addition, bee queens (which enjoy long lifespan as well as super fertility and physical qualities) consume royal jelly throughout their entire lives, and royal jelly is considered a promising anti-aging nutraceutical that can positively enhance fertility and improve body composition [2].\n\n2.2. Propolis: Its Constituents, Biological, and Pharmacological Activities\nPropolis, also known as bee glue, is a sticky wax-like substance that constitutes a mixture of bee salivary secretions, bee wax, and resinous sap occurring in the bark and leaf-buds of specific plants [37,65]. It comes in green, red, brown, or black colors based on the collected local flora [66]. The word propolis comprises two Greek words “pro” and “polis”, which in order mean “in front of or at the entrance to” and “community or city”. Propolis is a hive-defensive substance, which bees use to protect and repair their hives [67].\nPropolis is a unique product of a complex composition that comprises more than 420 chemical substances [37,68]. Nonetheless, its composition and biological activities vary considerably depending on its botanical and geographical origins as well as the time of harvesting [38,65,67]. Propolis is rich in oxyprenylated phenylpropanoids—secondary metabolites from plants, fungi, and bacteria [69]—such as 7-isopentenyloxucoumarin, boropinic acid, 4-geranyloxyferulic acid, and auraptene. The last two exist in raw Italian propolis at high concentrations: 107.12 and 145.37 μg/g of dry propolis, respectively. Flavonoids, a large group of phenolic compounds, are abundant in Italian propolis, and they are differentiated into several groups including flavanones (e.g., naringenine, 4.4 mg/g), flavones (e.g., apigenine, 1.7 mg/g), flavonols (e.g., galaning, 0.9 mg/g), tannins (e.g., gallic acid 8.4 mg/g), catechins (expressed as (+)-catechin 0.4 mg/g, and caffeic acid and its esters (expressed as caffeic acid, 9.2 mg/g) [69]. The most profuse flavonoids in ethanolic extracts of Brazilian propolis are artepillin C (38.6 mg/g), coumaric acid (10.6 mg/g), and kaempferide (12.6 mg/g) [70]. Key other constituents of propolis include polyphenol (e.g., phenolic acids and aromatic esters), phenolic aldehydes, terpenoids, ketones, enzymes (e.g., α- and β-amylase), vitamins (e.g., thiamin (B1), riboflavin (B2), pyridoxine (B6), ascorbic acid (C), tocopherol (E)), minerals (e.g., calcium, potassium, magnesium, iron, sodium, barium) essential oils, alcohol, fatty acids, β-steroids, and many other elements [37,38,67,68,71].\nThe attention of several drug targeting studies has recently been focused on the therapeutic activities of individual bioactive compounds in propolis [65,68]. Flavonoids comprise the majority of mostly studies bioactive substances in propolis. Chrysin (5,7-dihydroxyflavone) is a flavonoid that exists in certain mushrooms, flowers (e.g., blue passion flower), and in other bee products (e.g., honey). It expresses anti-inflammatory, antioxidant, anti-proliferative, and neuroprotective effects [72]. Caffeic acid phenethyl ester (CAPE), a derivative of hydroxycinnamic acid, expresses anti-oxidant, immunomodulatory, anti-inflammatory, antiviral, and ant-neoplastic properties [73,74,75]. Pinocembrin (5,7-dihydroxyflavanone) is the most copious flavonoid in propolis—1 g of balsam/an ethanolic extract from poplar propolis found in Spain contains up to 606–701 mg of pinocembrin [76]. It exists in numerous plants (e.g., Eucalyptus and Populus). It exhibits anti-inflammatory, antioxidant, antimicrobial, and antiproliferative activities [77,78].\nEssential/volatile oils are major bioactive constituents of propolis, and they contribute to its special aroma [79,80]. They also, partially, contribute to the strong antimicrobial, antioxidant, and anticancer activities of propolis [79,81,82]. The volatile fraction of propolis varies in each sample even within a single country due to plant source and climate [79]. For instance, cumulative knowledge shows that volatile oils in propolis found in countries surrounding the Mediterranean depend mainly on the botanical origin. They primarily comprise poplar-derived compounds (e.g., benzoic acid and its esters and oxygenated sesquiterpene β-eudesmol) and conifer-derived compounds such as the hydrocarbon monoterpene α-pinene [80]. Interestingly, the number of volatile compounds derived from a single type of propolis is also reported to vary according to extraction techniques. In this regard, reports from China show that traditional hydrodistillation, steam-distillation extraction, and dynamic headspace sampling could characterize around 12, 40 and 70 type of volatile components of propolis, respectively [79]. Moreover, the level of antimicrobial activity of volatile compounds of propolis greatly depends on their extent of purification [82].\nThanks to its countless bioactive elements, propolis enjoys a range of versatile biological and pharmacological properties including antimicrobial, antiviral, antifungal, antioxidant, anti-inflammatory, antineoplastic, antiaging, and cytostatic properties. In addition, it is considered a perfect natural food preservative due to its antimicrobial activity [35,38,65,66,68,71]. Because of its enormous health-promoting activities, propolis is widely used as a dietary supplement in many countries, especially in Japan [37,38,39].\nPropolis is not suitable for use in its crude state since it may contact harmful materials e.g., asphalt from the road [68]. Using solvents like ethanol, glycerol, chloroform, ether and acetone or water is necessary to get rid of hazardous substances and to increase its yield of bioactive compounds [67,68]. Although water may be a cheap solvent, propolis has poor solubility in water. Therefore, propolis water extracts are 10-fold lower in their phenolic contents than ethanol extracts. In addition, they retain the strong flavor and aroma of propolis [68]. Moreover, propolis contains allergenic components: caffeic acids derivates (e.g., 3-methyl-2-butenyl caffeate and phenylethyl caffeate), as well as benzyl salicylate and benzyl cinnamate [80]. Therefore, propolis use/consumption should be contraindicated in individuals with known allergies.\n\n2.3. Bee Pollen: Its Constituents, Biological, and Pharmacological Activities\nBee pollen is an api-material that originally comprises male gametophytes or spermatophytes of flowers, which stick to bee body. Bee workers mix these floral pollens with honey, nectar, and bee saliva. The latter is rich in various enzymes e.g., amylase, catalase, as well as lactic acid bacteria, which cause pollen fermentation [36,83,84]. Hence, the tiny wind pollen grains collected by bees aggregate together to form granules or pellets of 1.4–4 mm in size [84].\nIn addition to water, which in order constitutes 20–30% and 6–8% of the content of recently collected and dried bee pollen, bee pollen contains around 200 chemical compounds. Like other bee products, its composition varies considerably according to botanical origin. Carbohydrates account for the most abundant ingredient (18.50–84.25%), and reducing sugars such as glucose, fructose, and sucrose constitute the vastest majority (13–55%). Other major elements include proteins and essential amino acids (5–60%), unsaturated and saturated fatty acids (0.15–31.26%), crude fiber (0.3–20%), nucleic acids (especially RNA), and various minerals (e.g., potassium, phosphorus, calcium, magnesium, zinc, copper, manganese, and iron) [36,83,84,85,86]. In addition, its average total phenolic content is 30.59 mg gallic acid equivalents (GAE)/g, but again it varies considerably based on floral origin (0.69–213.20 mg GAE/g) [86]. Moreover, bee pollen is abundant in both water- and fat-soluble vitamins e.g., β-carotene (vitamin A precursor), ascorbic acid (C), tocopherol (E), folic acid (B9), and other vitamin B, especially niacin. Bee pollen contains other elements that still need to be explored (2–5%) [83]. Therefore, bee pollen represents a perfect whole health-promoting food. In fact, comparisons of the percentages of nutrients in bee pollen with daily required intake of an adult individual revealed that few grams of bee pollen can meet daily human nutritional requirements [83,84].\nBee pollen demonstrates various biological properties and therapeutic activities e.g., antioxidant, anti-inflammatory, anti-lipidemic, anticancer, antiallergic, and antimicrobial [36,87]. Existing knowledge emphasizes its antiaging effects: it reduced the production of age-related pigment known as lipofuscin (induced by oral peroxidized corn oil or intravenous alloxan injection) in cardiac muscle, brain, liver, and suprarenal gland in aged mice (reviewed in [34]).\nThe composition of bee pollens depends primarily on its botanical source since nutrient contents (e.g., polyphenols) of pollen grains, which support their survival and fusion with female gametes, vary between different plants [83,84]. Storage conditions are of great importance were it to retain its biological activities. Bee pollen should be consumed fresh soon after collection. Most of its major elements (reducing sugars, total proteins, vitamin C, and provitamin A) are destroyed at 40 °C. Lyophilization damages its vitamin content while freezing is recommended for the storage of bee pollen since it does not affect its chemical structure [83].\nDry pollen pellets resist decay due to their tough outer coat, which comprises two layers made of cellulose and sporopollenin [88,89]. However, ingestion of bee pollen by humans may not yield its optimal nutritional value because the hard sporopollenin shell hinders access of digestive secretions to the nutrient-rich core of the pellet. Biological, chemical, and mechanical techniques are used to break bee pollen microcapsules in order to enhance its digestibility in the gut. However, these methods may be expensive or ineffective i.e., they degrade important nutrients via enzymatic activity [88,90]. Ultraviolet spectroscopy and high performance liquid chromatography-photo diode array show that processing bee pollen through the use of an edible lipid-surfactant mixture (Captex 355 and Tween 80) increases its yield of polyphenols and flavonoid aglycones [90].\n\n2.4. Safety Profile of Royal Jelly, Propolis, and Bee Pollen\nPropolis exists in a plethora of commercial products that are directly consumed or used by humans e.g., lozenges, soap, toothpastes and mouth wash, creams, gels, cough syrups, wines, cakes, chewing gums, candies, shampoo, chocolate, skin lotions, processed meat, etc. [67]. In addition, royal jelly, bee pollen, and propolis are widely used as dietary supplements in many parts of the world [36,37,38,39]. Existing knowledge denotes no adverse effects from their consumption either in rodents or in humans [39,66]. The safety of pinocembrin, a flavonoid available in propolis and an approved drug in China, is documented since its elimination from the body is rapid [91]. The safety profile of bee pollen (both crude and processed) has been empirically tested. Oral consumption of bee pollen (up to 2 g/kg body weight) expressed no allergic reactions in mice including behavioral changes, salivation, diarrhea, respiratory or autonomic responses, restlessness, convulsions, tremors, or death [90]. In fact, the German Federal Board of Health acknowledges bee pollen as an official medicine [36].\nSeveral lines of evidence support the anti-allergic effect of propolis and royal jelly. This effect involves inhibiting mast cell degranulation, suppressing cysteinyl-leukotriene release, as well as reducing serum histamine, IgG, and IgE levels in various allergic conditions by suppressing histamine H1 receptor [37,39,92]. Nevertheless, rare allergic reactions to bee products other than bee venom are documented in the literature. They are most frequent in small children [80,93]. Examples of such reactions comprise contact dermatitis in beekeepers following the handling of propolis, as well as contact stomatitis and oral mucositis after the usage of lozenges containing propolis [80]. Hence, bee products should be used with caution, especially in people with known allergies, pregnant and lactating women, and small children [61]. In addition, bee products can be safely consumed after adequate processing. Processing involves removal of known allergens such as enzyme treatment of royal jelly and filtration of bee venom by stepped-gradient open column [2,94]."}

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T30536","span":{"begin":1502,"end":1507},"obj":"http://purl.obolibrary.org/obo/GO_0007568"},{"id":"T48260","span":{"begin":2160,"end":2165},"obj":"http://purl.obolibrary.org/obo/GO_0007568"},{"id":"T99024","span":{"begin":2382,"end":2387},"obj":"http://purl.obolibrary.org/obo/GO_0007568"},{"id":"T2268","span":{"begin":4353,"end":4371},"obj":"http://purl.obolibrary.org/obo/GO_0008283"},{"id":"T29579","span":{"begin":4373,"end":4386},"obj":"http://purl.obolibrary.org/obo/GO_0007155"},{"id":"T67133","span":{"begin":4388,"end":4399},"obj":"http://purl.obolibrary.org/obo/GO_0016049"},{"id":"T56275","span":{"begin":4393,"end":4399},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T82150","span":{"begin":5238,"end":5244},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T17533","span":{"begin":5303,"end":5321},"obj":"http://purl.obolibrary.org/obo/GO_0007165"},{"id":"T62332","span":{"begin":5303,"end":5312},"obj":"http://purl.obolibrary.org/obo/GO_0023052"},{"id":"T25963","span":{"begin":6085,"end":6090},"obj":"http://purl.obolibrary.org/obo/GO_0007568"},{"id":"T1068","span":{"begin":8257,"end":8262},"obj":"http://purl.obolibrary.org/obo/GO_0007568"},{"id":"T58157","span":{"begin":8534,"end":8544},"obj":"http://purl.obolibrary.org/obo/GO_0046903"},{"id":"T1876","span":{"begin":14668,"end":14680},"obj":"http://purl.obolibrary.org/obo/GO_0006113"},{"id":"T35202","span":{"begin":17011,"end":17018},"obj":"http://purl.obolibrary.org/obo/GO_0051235"},{"id":"T8005","span":{"begin":17353,"end":17360},"obj":"http://purl.obolibrary.org/obo/GO_0051235"},{"id":"T10207","span":{"begin":17716,"end":17726},"obj":"http://purl.obolibrary.org/obo/GO_0046903"},{"id":"T70492","span":{"begin":18550,"end":18557},"obj":"http://purl.obolibrary.org/obo/GO_0071626"},{"id":"T63608","span":{"begin":19249,"end":19259},"obj":"http://purl.obolibrary.org/obo/GO_0046541"},{"id":"T33","span":{"begin":19565,"end":19599},"obj":"http://purl.obolibrary.org/obo/GO_0043305"},{"id":"T34","span":{"begin":19576,"end":19599},"obj":"http://purl.obolibrary.org/obo/GO_0043303"}],"text":"2. Apitherapy as a Possible Complementary Treatment for Sarcopenia\nRock paintings from the Stone Age portray consumption of bee products by humans [27]. The first evidence of human usage of bee products for therapeutic and cosmetic purposes dates back 6000 years in ancient Egypt and later in China, Greece, and Rome [27,28,29,30]. Current research interest is directed toward the use of natural substances, including bee products, as potential pharmaceuticals to modify disease progression [31]. The term “apitherapy” describes a category of complementary and alternative medicine that comprises therapeutic use of various bee products including apilarnil (atomized drone larva) to prevent and treat illnesses [30].\nBee workers of either Apis mellifera or Apis cerana species—the former is common in Europe, Asia, Africa, and America while the latter exists only in southern and southeastern Asia—produce and store multiple bioactive substances [32]. Royal jelly, propolis, bee pollen, honey, bee venom, bee bread, and bee wax are common products of the bee hive. They all (to a varying degree) possess multiple health promoting properties due to their high content of natural antioxidants such as flavonoids, phenols, or terpenoids [28,32]. Research documents variability in contents and effects of every single bee product, mainly due to the influence of bee species, botanical origin, geographic location, season, extraction, and handling procedures [2,28].\nSeveral lines of evidence describe anti-aging effects of royal jelly, bee pollen, and propolis both in humans and laboratory animals [2,33,34,35]. These three products are widely used as dietary supplements [36,37,38,39]. In the meantime, the literature gives examples of numerous dietary supplements that could successfully prevent or alleviate the progression of muscle mass loss in old age [40,41,42]. Bee products represent a part of this interventional strategy. However, the extent to which bee products can affect sarcopenia as well as understanding of their underlying mechanism of action are far from being clear. Therefore, we conducted this review with the aim of investigating the anti-aging properties of these products with a focus on skeletal muscle functioning in advanced age. In this respect, we reviewed animal and human studies investigating effects of the aforementioned products on skeletal muscle aging and elaborated on different mechanisms underlying these effects. Studies included in this review were retrieved by searching PubMed and Google scholar using a combination of terminologies of “sarcopenia, muscle wasting, muscle mass, lean body mass, skeletal muscle, motor” with “royal jelly, honey, bee pollen, propolis, bee venom, bee bread, bee wax, chrysin, apamin, caffeic acid phenethyl ester”. Snow ball manual search using reference lists of retrieved studies was also conducted. This search resulted in a number of studies, which addressed muscle wasting and related dynamics through the use of three bee products, namely royal jelly, bee pollen, and propolis. Figure 1, Panel A and Panel B, summarizes the chemical composition and biological properties of these bee products while this section elaborates on these products in depth.\n\n2.1. Royal Jelly: Its Constituents, Biological, and Pharmacological Activities\nRoyal jelly is a thick, milky, white-yellowish, acidic colloid substance secreted from the hypopharyngeal and mandibular salivary glands of young nurse honey bees (5–15 days old) [32,43]. In general, fresh royal jelly mostly consists of water (67% w/w) in addition to carbohydrates (16%), proteins and amino acids (12.5%), fat (5%), and many other elements [32]. However, royal jelly content of these substances noticeably varies depending on numerous factors like botanical source, bee species, bee artificial feeding, weather, season, location, method of processing, and the like [2,44].\nProtein is the most copious active element in royal jelly, representing half the weight of its dry matter [2]. It vastly comprises nine 49–87 kDa water-insoluble proteins, known as major royal jelly proteins 1–9 (MRJPs1-9) [2,45]. MRJPs constitute more than 80% of royal jelly protein content, and MRJPs1–5 constitute 82–90% of all MRJPs. MRJPs contain 400–578 amino acids that contribute to the antioxidant effect of royal jelly as well as its role in cell proliferation, cell adhesion, cell growth, and immunity [46,47]. Novel non-MRJPs proteins have been newly discovered [48]. Royalisin, jelleines, and aspimin are examples of other proteins that exist in royal jelly, albeit in small amounts. These proteins as well as MRJPs demonstrate strong antimicrobial and bactericidal activities even against the most drug-resistant bacterial strains such as methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, vancomycin-resistant Enterococci, as well as extended-spectrum β-lactamase-producing Proteus mirabilis and Escherichia coli [28,29].\nCarbohydrates (e.g., fructose, glucose maltose, trehalose, melibiose, ribose, and erlose) constitute 7.5–16% or royal jelly content [49]. Reducing sugars in royal jelly are thought to contribute to its epigenetic effect through the activation of insulin-like growth factor 1 (IGF-1) and mammalian target of rapamycin (mTOR) signaling cascades. Thus, they stimulate caste differentiation of Apis mellifera larvae into queens by increasing intake of food and key nutrients [50].\nLipids make up 7–18% of the dry weight of royal jelly. This fraction largely comprises a group of unique and rare saturated or monounsaturated short and medium chain fatty acids that are terminally or internally hydroxylated with terminal mono- or dicarboxylic acid functions [2,28]. The vast majority of royal jelly fat content (80–85%) consists of short hydroxyl fatty acids such as trans-10-hydroxy-2-decenoic acid (10-HDA), which exists only in royal jelly; and therefore, it is known as royal jelly acid or queen bee acid [28,49,51]. 10-HDA is one of the most potent bioactive elements in royal jelly expressing strong anti-aging, neuroprotective, antiproliferative, antimicrobial, antioxidant, anti-inflammatory, and epigenetic effects [52,53,54,55,56,57,58]. In addition, the lipid fraction of royal jelly contains phenolic acids (4–10%), wax (5–6%), steroids (3–4%), and phospholipids (0.4–0.8%) [49].\nA wide range of minor constituents and bioactive compounds exist profusely in royal jelly such as acetylcholine, nucleotides (adenosine, guanosine, adenosine tri-phosphate (ATP), adenosine monophosphate (AMP)), minerals (iron, sodium, calcium, potassium, zinc, magnesium, manganese, and copper), amino acids (8 out of 9 essential amino acids Val, Leu, Ile, Thr, Met, Phe, Lys, and Trp), vitamins (retinol (A), ascorbic acid (C), tocopherol (E), riboflavin (B2), niacin (B3), and other B vitamins), esters, aldehydes, ketones, alcohol, and minor heterocyclic compounds [2,28,49,59,60,61]. It is worth noting that royal jelly loses most of its bioactive ingredients and biological properties when stored at a temperature of 5 °C or higher. Therefore, freezing is the best method to store royal jelly [62]. Enzymatic treatment of royal jelly removes allergen proteins and enhances its nutrient content in addition to improving its digestibility and absorption in the gut without altering its freshness [2,59].\nRoyal jelly has been historically used as a beautifying agent by famous queens such as Cleopatra, and it is still involved in the cosmetic industry [29,56]. Its rich content of bioactive compounds grants it a plethora of diverse health benefits such as antioxidant, anti-inflammatory, neurotrophic, hypotensive, antidiabetic, antilipidemic, antirheumatic, anticarcinogenic, anti-fatigue, antiadipogenic, and antimicrobial activities [43,45,63]. Therefore, it is widely used to treat multiple serious conditions including diabetes, hypertension, hyperlipidemia, cancer, skin diseases, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease [2,43,46,59,64]. In addition, bee queens (which enjoy long lifespan as well as super fertility and physical qualities) consume royal jelly throughout their entire lives, and royal jelly is considered a promising anti-aging nutraceutical that can positively enhance fertility and improve body composition [2].\n\n2.2. Propolis: Its Constituents, Biological, and Pharmacological Activities\nPropolis, also known as bee glue, is a sticky wax-like substance that constitutes a mixture of bee salivary secretions, bee wax, and resinous sap occurring in the bark and leaf-buds of specific plants [37,65]. It comes in green, red, brown, or black colors based on the collected local flora [66]. The word propolis comprises two Greek words “pro” and “polis”, which in order mean “in front of or at the entrance to” and “community or city”. Propolis is a hive-defensive substance, which bees use to protect and repair their hives [67].\nPropolis is a unique product of a complex composition that comprises more than 420 chemical substances [37,68]. Nonetheless, its composition and biological activities vary considerably depending on its botanical and geographical origins as well as the time of harvesting [38,65,67]. Propolis is rich in oxyprenylated phenylpropanoids—secondary metabolites from plants, fungi, and bacteria [69]—such as 7-isopentenyloxucoumarin, boropinic acid, 4-geranyloxyferulic acid, and auraptene. The last two exist in raw Italian propolis at high concentrations: 107.12 and 145.37 μg/g of dry propolis, respectively. Flavonoids, a large group of phenolic compounds, are abundant in Italian propolis, and they are differentiated into several groups including flavanones (e.g., naringenine, 4.4 mg/g), flavones (e.g., apigenine, 1.7 mg/g), flavonols (e.g., galaning, 0.9 mg/g), tannins (e.g., gallic acid 8.4 mg/g), catechins (expressed as (+)-catechin 0.4 mg/g, and caffeic acid and its esters (expressed as caffeic acid, 9.2 mg/g) [69]. The most profuse flavonoids in ethanolic extracts of Brazilian propolis are artepillin C (38.6 mg/g), coumaric acid (10.6 mg/g), and kaempferide (12.6 mg/g) [70]. Key other constituents of propolis include polyphenol (e.g., phenolic acids and aromatic esters), phenolic aldehydes, terpenoids, ketones, enzymes (e.g., α- and β-amylase), vitamins (e.g., thiamin (B1), riboflavin (B2), pyridoxine (B6), ascorbic acid (C), tocopherol (E)), minerals (e.g., calcium, potassium, magnesium, iron, sodium, barium) essential oils, alcohol, fatty acids, β-steroids, and many other elements [37,38,67,68,71].\nThe attention of several drug targeting studies has recently been focused on the therapeutic activities of individual bioactive compounds in propolis [65,68]. Flavonoids comprise the majority of mostly studies bioactive substances in propolis. Chrysin (5,7-dihydroxyflavone) is a flavonoid that exists in certain mushrooms, flowers (e.g., blue passion flower), and in other bee products (e.g., honey). It expresses anti-inflammatory, antioxidant, anti-proliferative, and neuroprotective effects [72]. Caffeic acid phenethyl ester (CAPE), a derivative of hydroxycinnamic acid, expresses anti-oxidant, immunomodulatory, anti-inflammatory, antiviral, and ant-neoplastic properties [73,74,75]. Pinocembrin (5,7-dihydroxyflavanone) is the most copious flavonoid in propolis—1 g of balsam/an ethanolic extract from poplar propolis found in Spain contains up to 606–701 mg of pinocembrin [76]. It exists in numerous plants (e.g., Eucalyptus and Populus). It exhibits anti-inflammatory, antioxidant, antimicrobial, and antiproliferative activities [77,78].\nEssential/volatile oils are major bioactive constituents of propolis, and they contribute to its special aroma [79,80]. They also, partially, contribute to the strong antimicrobial, antioxidant, and anticancer activities of propolis [79,81,82]. The volatile fraction of propolis varies in each sample even within a single country due to plant source and climate [79]. For instance, cumulative knowledge shows that volatile oils in propolis found in countries surrounding the Mediterranean depend mainly on the botanical origin. They primarily comprise poplar-derived compounds (e.g., benzoic acid and its esters and oxygenated sesquiterpene β-eudesmol) and conifer-derived compounds such as the hydrocarbon monoterpene α-pinene [80]. Interestingly, the number of volatile compounds derived from a single type of propolis is also reported to vary according to extraction techniques. In this regard, reports from China show that traditional hydrodistillation, steam-distillation extraction, and dynamic headspace sampling could characterize around 12, 40 and 70 type of volatile components of propolis, respectively [79]. Moreover, the level of antimicrobial activity of volatile compounds of propolis greatly depends on their extent of purification [82].\nThanks to its countless bioactive elements, propolis enjoys a range of versatile biological and pharmacological properties including antimicrobial, antiviral, antifungal, antioxidant, anti-inflammatory, antineoplastic, antiaging, and cytostatic properties. In addition, it is considered a perfect natural food preservative due to its antimicrobial activity [35,38,65,66,68,71]. Because of its enormous health-promoting activities, propolis is widely used as a dietary supplement in many countries, especially in Japan [37,38,39].\nPropolis is not suitable for use in its crude state since it may contact harmful materials e.g., asphalt from the road [68]. Using solvents like ethanol, glycerol, chloroform, ether and acetone or water is necessary to get rid of hazardous substances and to increase its yield of bioactive compounds [67,68]. Although water may be a cheap solvent, propolis has poor solubility in water. Therefore, propolis water extracts are 10-fold lower in their phenolic contents than ethanol extracts. In addition, they retain the strong flavor and aroma of propolis [68]. Moreover, propolis contains allergenic components: caffeic acids derivates (e.g., 3-methyl-2-butenyl caffeate and phenylethyl caffeate), as well as benzyl salicylate and benzyl cinnamate [80]. Therefore, propolis use/consumption should be contraindicated in individuals with known allergies.\n\n2.3. Bee Pollen: Its Constituents, Biological, and Pharmacological Activities\nBee pollen is an api-material that originally comprises male gametophytes or spermatophytes of flowers, which stick to bee body. Bee workers mix these floral pollens with honey, nectar, and bee saliva. The latter is rich in various enzymes e.g., amylase, catalase, as well as lactic acid bacteria, which cause pollen fermentation [36,83,84]. Hence, the tiny wind pollen grains collected by bees aggregate together to form granules or pellets of 1.4–4 mm in size [84].\nIn addition to water, which in order constitutes 20–30% and 6–8% of the content of recently collected and dried bee pollen, bee pollen contains around 200 chemical compounds. Like other bee products, its composition varies considerably according to botanical origin. Carbohydrates account for the most abundant ingredient (18.50–84.25%), and reducing sugars such as glucose, fructose, and sucrose constitute the vastest majority (13–55%). Other major elements include proteins and essential amino acids (5–60%), unsaturated and saturated fatty acids (0.15–31.26%), crude fiber (0.3–20%), nucleic acids (especially RNA), and various minerals (e.g., potassium, phosphorus, calcium, magnesium, zinc, copper, manganese, and iron) [36,83,84,85,86]. In addition, its average total phenolic content is 30.59 mg gallic acid equivalents (GAE)/g, but again it varies considerably based on floral origin (0.69–213.20 mg GAE/g) [86]. Moreover, bee pollen is abundant in both water- and fat-soluble vitamins e.g., β-carotene (vitamin A precursor), ascorbic acid (C), tocopherol (E), folic acid (B9), and other vitamin B, especially niacin. Bee pollen contains other elements that still need to be explored (2–5%) [83]. Therefore, bee pollen represents a perfect whole health-promoting food. In fact, comparisons of the percentages of nutrients in bee pollen with daily required intake of an adult individual revealed that few grams of bee pollen can meet daily human nutritional requirements [83,84].\nBee pollen demonstrates various biological properties and therapeutic activities e.g., antioxidant, anti-inflammatory, anti-lipidemic, anticancer, antiallergic, and antimicrobial [36,87]. Existing knowledge emphasizes its antiaging effects: it reduced the production of age-related pigment known as lipofuscin (induced by oral peroxidized corn oil or intravenous alloxan injection) in cardiac muscle, brain, liver, and suprarenal gland in aged mice (reviewed in [34]).\nThe composition of bee pollens depends primarily on its botanical source since nutrient contents (e.g., polyphenols) of pollen grains, which support their survival and fusion with female gametes, vary between different plants [83,84]. Storage conditions are of great importance were it to retain its biological activities. Bee pollen should be consumed fresh soon after collection. Most of its major elements (reducing sugars, total proteins, vitamin C, and provitamin A) are destroyed at 40 °C. Lyophilization damages its vitamin content while freezing is recommended for the storage of bee pollen since it does not affect its chemical structure [83].\nDry pollen pellets resist decay due to their tough outer coat, which comprises two layers made of cellulose and sporopollenin [88,89]. However, ingestion of bee pollen by humans may not yield its optimal nutritional value because the hard sporopollenin shell hinders access of digestive secretions to the nutrient-rich core of the pellet. Biological, chemical, and mechanical techniques are used to break bee pollen microcapsules in order to enhance its digestibility in the gut. However, these methods may be expensive or ineffective i.e., they degrade important nutrients via enzymatic activity [88,90]. Ultraviolet spectroscopy and high performance liquid chromatography-photo diode array show that processing bee pollen through the use of an edible lipid-surfactant mixture (Captex 355 and Tween 80) increases its yield of polyphenols and flavonoid aglycones [90].\n\n2.4. Safety Profile of Royal Jelly, Propolis, and Bee Pollen\nPropolis exists in a plethora of commercial products that are directly consumed or used by humans e.g., lozenges, soap, toothpastes and mouth wash, creams, gels, cough syrups, wines, cakes, chewing gums, candies, shampoo, chocolate, skin lotions, processed meat, etc. [67]. In addition, royal jelly, bee pollen, and propolis are widely used as dietary supplements in many parts of the world [36,37,38,39]. Existing knowledge denotes no adverse effects from their consumption either in rodents or in humans [39,66]. The safety of pinocembrin, a flavonoid available in propolis and an approved drug in China, is documented since its elimination from the body is rapid [91]. The safety profile of bee pollen (both crude and processed) has been empirically tested. Oral consumption of bee pollen (up to 2 g/kg body weight) expressed no allergic reactions in mice including behavioral changes, salivation, diarrhea, respiratory or autonomic responses, restlessness, convulsions, tremors, or death [90]. In fact, the German Federal Board of Health acknowledges bee pollen as an official medicine [36].\nSeveral lines of evidence support the anti-allergic effect of propolis and royal jelly. This effect involves inhibiting mast cell degranulation, suppressing cysteinyl-leukotriene release, as well as reducing serum histamine, IgG, and IgE levels in various allergic conditions by suppressing histamine H1 receptor [37,39,92]. Nevertheless, rare allergic reactions to bee products other than bee venom are documented in the literature. They are most frequent in small children [80,93]. Examples of such reactions comprise contact dermatitis in beekeepers following the handling of propolis, as well as contact stomatitis and oral mucositis after the usage of lozenges containing propolis [80]. Hence, bee products should be used with caution, especially in people with known allergies, pregnant and lactating women, and small children [61]. In addition, bee products can be safely consumed after adequate processing. Processing involves removal of known allergens such as enzyme treatment of royal jelly and filtration of bee venom by stepped-gradient open column [2,94]."}

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Apitherapy as a Possible Complementary Treatment for Sarcopenia\nRock paintings from the Stone Age portray consumption of bee products by humans [27]. The first evidence of human usage of bee products for therapeutic and cosmetic purposes dates back 6000 years in ancient Egypt and later in China, Greece, and Rome [27,28,29,30]. Current research interest is directed toward the use of natural substances, including bee products, as potential pharmaceuticals to modify disease progression [31]. The term “apitherapy” describes a category of complementary and alternative medicine that comprises therapeutic use of various bee products including apilarnil (atomized drone larva) to prevent and treat illnesses [30].\nBee workers of either Apis mellifera or Apis cerana species—the former is common in Europe, Asia, Africa, and America while the latter exists only in southern and southeastern Asia—produce and store multiple bioactive substances [32]. Royal jelly, propolis, bee pollen, honey, bee venom, bee bread, and bee wax are common products of the bee hive. They all (to a varying degree) possess multiple health promoting properties due to their high content of natural antioxidants such as flavonoids, phenols, or terpenoids [28,32]. Research documents variability in contents and effects of every single bee product, mainly due to the influence of bee species, botanical origin, geographic location, season, extraction, and handling procedures [2,28].\nSeveral lines of evidence describe anti-aging effects of royal jelly, bee pollen, and propolis both in humans and laboratory animals [2,33,34,35]. These three products are widely used as dietary supplements [36,37,38,39]. In the meantime, the literature gives examples of numerous dietary supplements that could successfully prevent or alleviate the progression of muscle mass loss in old age [40,41,42]. Bee products represent a part of this interventional strategy. However, the extent to which bee products can affect sarcopenia as well as understanding of their underlying mechanism of action are far from being clear. Therefore, we conducted this review with the aim of investigating the anti-aging properties of these products with a focus on skeletal muscle functioning in advanced age. In this respect, we reviewed animal and human studies investigating effects of the aforementioned products on skeletal muscle aging and elaborated on different mechanisms underlying these effects. Studies included in this review were retrieved by searching PubMed and Google scholar using a combination of terminologies of “sarcopenia, muscle wasting, muscle mass, lean body mass, skeletal muscle, motor” with “royal jelly, honey, bee pollen, propolis, bee venom, bee bread, bee wax, chrysin, apamin, caffeic acid phenethyl ester”. Snow ball manual search using reference lists of retrieved studies was also conducted. This search resulted in a number of studies, which addressed muscle wasting and related dynamics through the use of three bee products, namely royal jelly, bee pollen, and propolis. Figure 1, Panel A and Panel B, summarizes the chemical composition and biological properties of these bee products while this section elaborates on these products in depth.\n\n2.1. Royal Jelly: Its Constituents, Biological, and Pharmacological Activities\nRoyal jelly is a thick, milky, white-yellowish, acidic colloid substance secreted from the hypopharyngeal and mandibular salivary glands of young nurse honey bees (5–15 days old) [32,43]. In general, fresh royal jelly mostly consists of water (67% w/w) in addition to carbohydrates (16%), proteins and amino acids (12.5%), fat (5%), and many other elements [32]. However, royal jelly content of these substances noticeably varies depending on numerous factors like botanical source, bee species, bee artificial feeding, weather, season, location, method of processing, and the like [2,44].\nProtein is the most copious active element in royal jelly, representing half the weight of its dry matter [2]. It vastly comprises nine 49–87 kDa water-insoluble proteins, known as major royal jelly proteins 1–9 (MRJPs1-9) [2,45]. MRJPs constitute more than 80% of royal jelly protein content, and MRJPs1–5 constitute 82–90% of all MRJPs. MRJPs contain 400–578 amino acids that contribute to the antioxidant effect of royal jelly as well as its role in cell proliferation, cell adhesion, cell growth, and immunity [46,47]. Novel non-MRJPs proteins have been newly discovered [48]. Royalisin, jelleines, and aspimin are examples of other proteins that exist in royal jelly, albeit in small amounts. These proteins as well as MRJPs demonstrate strong antimicrobial and bactericidal activities even against the most drug-resistant bacterial strains such as methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, vancomycin-resistant Enterococci, as well as extended-spectrum β-lactamase-producing Proteus mirabilis and Escherichia coli [28,29].\nCarbohydrates (e.g., fructose, glucose maltose, trehalose, melibiose, ribose, and erlose) constitute 7.5–16% or royal jelly content [49]. Reducing sugars in royal jelly are thought to contribute to its epigenetic effect through the activation of insulin-like growth factor 1 (IGF-1) and mammalian target of rapamycin (mTOR) signaling cascades. Thus, they stimulate caste differentiation of Apis mellifera larvae into queens by increasing intake of food and key nutrients [50].\nLipids make up 7–18% of the dry weight of royal jelly. This fraction largely comprises a group of unique and rare saturated or monounsaturated short and medium chain fatty acids that are terminally or internally hydroxylated with terminal mono- or dicarboxylic acid functions [2,28]. The vast majority of royal jelly fat content (80–85%) consists of short hydroxyl fatty acids such as trans-10-hydroxy-2-decenoic acid (10-HDA), which exists only in royal jelly; and therefore, it is known as royal jelly acid or queen bee acid [28,49,51]. 10-HDA is one of the most potent bioactive elements in royal jelly expressing strong anti-aging, neuroprotective, antiproliferative, antimicrobial, antioxidant, anti-inflammatory, and epigenetic effects [52,53,54,55,56,57,58]. In addition, the lipid fraction of royal jelly contains phenolic acids (4–10%), wax (5–6%), steroids (3–4%), and phospholipids (0.4–0.8%) [49].\nA wide range of minor constituents and bioactive compounds exist profusely in royal jelly such as acetylcholine, nucleotides (adenosine, guanosine, adenosine tri-phosphate (ATP), adenosine monophosphate (AMP)), minerals (iron, sodium, calcium, potassium, zinc, magnesium, manganese, and copper), amino acids (8 out of 9 essential amino acids Val, Leu, Ile, Thr, Met, Phe, Lys, and Trp), vitamins (retinol (A), ascorbic acid (C), tocopherol (E), riboflavin (B2), niacin (B3), and other B vitamins), esters, aldehydes, ketones, alcohol, and minor heterocyclic compounds [2,28,49,59,60,61]. It is worth noting that royal jelly loses most of its bioactive ingredients and biological properties when stored at a temperature of 5 °C or higher. Therefore, freezing is the best method to store royal jelly [62]. Enzymatic treatment of royal jelly removes allergen proteins and enhances its nutrient content in addition to improving its digestibility and absorption in the gut without altering its freshness [2,59].\nRoyal jelly has been historically used as a beautifying agent by famous queens such as Cleopatra, and it is still involved in the cosmetic industry [29,56]. Its rich content of bioactive compounds grants it a plethora of diverse health benefits such as antioxidant, anti-inflammatory, neurotrophic, hypotensive, antidiabetic, antilipidemic, antirheumatic, anticarcinogenic, anti-fatigue, antiadipogenic, and antimicrobial activities [43,45,63]. Therefore, it is widely used to treat multiple serious conditions including diabetes, hypertension, hyperlipidemia, cancer, skin diseases, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease [2,43,46,59,64]. In addition, bee queens (which enjoy long lifespan as well as super fertility and physical qualities) consume royal jelly throughout their entire lives, and royal jelly is considered a promising anti-aging nutraceutical that can positively enhance fertility and improve body composition [2].\n\n2.2. Propolis: Its Constituents, Biological, and Pharmacological Activities\nPropolis, also known as bee glue, is a sticky wax-like substance that constitutes a mixture of bee salivary secretions, bee wax, and resinous sap occurring in the bark and leaf-buds of specific plants [37,65]. It comes in green, red, brown, or black colors based on the collected local flora [66]. The word propolis comprises two Greek words “pro” and “polis”, which in order mean “in front of or at the entrance to” and “community or city”. Propolis is a hive-defensive substance, which bees use to protect and repair their hives [67].\nPropolis is a unique product of a complex composition that comprises more than 420 chemical substances [37,68]. Nonetheless, its composition and biological activities vary considerably depending on its botanical and geographical origins as well as the time of harvesting [38,65,67]. Propolis is rich in oxyprenylated phenylpropanoids—secondary metabolites from plants, fungi, and bacteria [69]—such as 7-isopentenyloxucoumarin, boropinic acid, 4-geranyloxyferulic acid, and auraptene. The last two exist in raw Italian propolis at high concentrations: 107.12 and 145.37 μg/g of dry propolis, respectively. Flavonoids, a large group of phenolic compounds, are abundant in Italian propolis, and they are differentiated into several groups including flavanones (e.g., naringenine, 4.4 mg/g), flavones (e.g., apigenine, 1.7 mg/g), flavonols (e.g., galaning, 0.9 mg/g), tannins (e.g., gallic acid 8.4 mg/g), catechins (expressed as (+)-catechin 0.4 mg/g, and caffeic acid and its esters (expressed as caffeic acid, 9.2 mg/g) [69]. The most profuse flavonoids in ethanolic extracts of Brazilian propolis are artepillin C (38.6 mg/g), coumaric acid (10.6 mg/g), and kaempferide (12.6 mg/g) [70]. Key other constituents of propolis include polyphenol (e.g., phenolic acids and aromatic esters), phenolic aldehydes, terpenoids, ketones, enzymes (e.g., α- and β-amylase), vitamins (e.g., thiamin (B1), riboflavin (B2), pyridoxine (B6), ascorbic acid (C), tocopherol (E)), minerals (e.g., calcium, potassium, magnesium, iron, sodium, barium) essential oils, alcohol, fatty acids, β-steroids, and many other elements [37,38,67,68,71].\nThe attention of several drug targeting studies has recently been focused on the therapeutic activities of individual bioactive compounds in propolis [65,68]. Flavonoids comprise the majority of mostly studies bioactive substances in propolis. Chrysin (5,7-dihydroxyflavone) is a flavonoid that exists in certain mushrooms, flowers (e.g., blue passion flower), and in other bee products (e.g., honey). It expresses anti-inflammatory, antioxidant, anti-proliferative, and neuroprotective effects [72]. Caffeic acid phenethyl ester (CAPE), a derivative of hydroxycinnamic acid, expresses anti-oxidant, immunomodulatory, anti-inflammatory, antiviral, and ant-neoplastic properties [73,74,75]. Pinocembrin (5,7-dihydroxyflavanone) is the most copious flavonoid in propolis—1 g of balsam/an ethanolic extract from poplar propolis found in Spain contains up to 606–701 mg of pinocembrin [76]. It exists in numerous plants (e.g., Eucalyptus and Populus). It exhibits anti-inflammatory, antioxidant, antimicrobial, and antiproliferative activities [77,78].\nEssential/volatile oils are major bioactive constituents of propolis, and they contribute to its special aroma [79,80]. They also, partially, contribute to the strong antimicrobial, antioxidant, and anticancer activities of propolis [79,81,82]. The volatile fraction of propolis varies in each sample even within a single country due to plant source and climate [79]. For instance, cumulative knowledge shows that volatile oils in propolis found in countries surrounding the Mediterranean depend mainly on the botanical origin. They primarily comprise poplar-derived compounds (e.g., benzoic acid and its esters and oxygenated sesquiterpene β-eudesmol) and conifer-derived compounds such as the hydrocarbon monoterpene α-pinene [80]. Interestingly, the number of volatile compounds derived from a single type of propolis is also reported to vary according to extraction techniques. In this regard, reports from China show that traditional hydrodistillation, steam-distillation extraction, and dynamic headspace sampling could characterize around 12, 40 and 70 type of volatile components of propolis, respectively [79]. Moreover, the level of antimicrobial activity of volatile compounds of propolis greatly depends on their extent of purification [82].\nThanks to its countless bioactive elements, propolis enjoys a range of versatile biological and pharmacological properties including antimicrobial, antiviral, antifungal, antioxidant, anti-inflammatory, antineoplastic, antiaging, and cytostatic properties. In addition, it is considered a perfect natural food preservative due to its antimicrobial activity [35,38,65,66,68,71]. Because of its enormous health-promoting activities, propolis is widely used as a dietary supplement in many countries, especially in Japan [37,38,39].\nPropolis is not suitable for use in its crude state since it may contact harmful materials e.g., asphalt from the road [68]. Using solvents like ethanol, glycerol, chloroform, ether and acetone or water is necessary to get rid of hazardous substances and to increase its yield of bioactive compounds [67,68]. Although water may be a cheap solvent, propolis has poor solubility in water. Therefore, propolis water extracts are 10-fold lower in their phenolic contents than ethanol extracts. In addition, they retain the strong flavor and aroma of propolis [68]. Moreover, propolis contains allergenic components: caffeic acids derivates (e.g., 3-methyl-2-butenyl caffeate and phenylethyl caffeate), as well as benzyl salicylate and benzyl cinnamate [80]. Therefore, propolis use/consumption should be contraindicated in individuals with known allergies.\n\n2.3. Bee Pollen: Its Constituents, Biological, and Pharmacological Activities\nBee pollen is an api-material that originally comprises male gametophytes or spermatophytes of flowers, which stick to bee body. Bee workers mix these floral pollens with honey, nectar, and bee saliva. The latter is rich in various enzymes e.g., amylase, catalase, as well as lactic acid bacteria, which cause pollen fermentation [36,83,84]. Hence, the tiny wind pollen grains collected by bees aggregate together to form granules or pellets of 1.4–4 mm in size [84].\nIn addition to water, which in order constitutes 20–30% and 6–8% of the content of recently collected and dried bee pollen, bee pollen contains around 200 chemical compounds. Like other bee products, its composition varies considerably according to botanical origin. Carbohydrates account for the most abundant ingredient (18.50–84.25%), and reducing sugars such as glucose, fructose, and sucrose constitute the vastest majority (13–55%). Other major elements include proteins and essential amino acids (5–60%), unsaturated and saturated fatty acids (0.15–31.26%), crude fiber (0.3–20%), nucleic acids (especially RNA), and various minerals (e.g., potassium, phosphorus, calcium, magnesium, zinc, copper, manganese, and iron) [36,83,84,85,86]. In addition, its average total phenolic content is 30.59 mg gallic acid equivalents (GAE)/g, but again it varies considerably based on floral origin (0.69–213.20 mg GAE/g) [86]. Moreover, bee pollen is abundant in both water- and fat-soluble vitamins e.g., β-carotene (vitamin A precursor), ascorbic acid (C), tocopherol (E), folic acid (B9), and other vitamin B, especially niacin. Bee pollen contains other elements that still need to be explored (2–5%) [83]. Therefore, bee pollen represents a perfect whole health-promoting food. In fact, comparisons of the percentages of nutrients in bee pollen with daily required intake of an adult individual revealed that few grams of bee pollen can meet daily human nutritional requirements [83,84].\nBee pollen demonstrates various biological properties and therapeutic activities e.g., antioxidant, anti-inflammatory, anti-lipidemic, anticancer, antiallergic, and antimicrobial [36,87]. Existing knowledge emphasizes its antiaging effects: it reduced the production of age-related pigment known as lipofuscin (induced by oral peroxidized corn oil or intravenous alloxan injection) in cardiac muscle, brain, liver, and suprarenal gland in aged mice (reviewed in [34]).\nThe composition of bee pollens depends primarily on its botanical source since nutrient contents (e.g., polyphenols) of pollen grains, which support their survival and fusion with female gametes, vary between different plants [83,84]. Storage conditions are of great importance were it to retain its biological activities. Bee pollen should be consumed fresh soon after collection. Most of its major elements (reducing sugars, total proteins, vitamin C, and provitamin A) are destroyed at 40 °C. Lyophilization damages its vitamin content while freezing is recommended for the storage of bee pollen since it does not affect its chemical structure [83].\nDry pollen pellets resist decay due to their tough outer coat, which comprises two layers made of cellulose and sporopollenin [88,89]. However, ingestion of bee pollen by humans may not yield its optimal nutritional value because the hard sporopollenin shell hinders access of digestive secretions to the nutrient-rich core of the pellet. Biological, chemical, and mechanical techniques are used to break bee pollen microcapsules in order to enhance its digestibility in the gut. However, these methods may be expensive or ineffective i.e., they degrade important nutrients via enzymatic activity [88,90]. Ultraviolet spectroscopy and high performance liquid chromatography-photo diode array show that processing bee pollen through the use of an edible lipid-surfactant mixture (Captex 355 and Tween 80) increases its yield of polyphenols and flavonoid aglycones [90].\n\n2.4. Safety Profile of Royal Jelly, Propolis, and Bee Pollen\nPropolis exists in a plethora of commercial products that are directly consumed or used by humans e.g., lozenges, soap, toothpastes and mouth wash, creams, gels, cough syrups, wines, cakes, chewing gums, candies, shampoo, chocolate, skin lotions, processed meat, etc. [67]. In addition, royal jelly, bee pollen, and propolis are widely used as dietary supplements in many parts of the world [36,37,38,39]. Existing knowledge denotes no adverse effects from their consumption either in rodents or in humans [39,66]. The safety of pinocembrin, a flavonoid available in propolis and an approved drug in China, is documented since its elimination from the body is rapid [91]. The safety profile of bee pollen (both crude and processed) has been empirically tested. Oral consumption of bee pollen (up to 2 g/kg body weight) expressed no allergic reactions in mice including behavioral changes, salivation, diarrhea, respiratory or autonomic responses, restlessness, convulsions, tremors, or death [90]. In fact, the German Federal Board of Health acknowledges bee pollen as an official medicine [36].\nSeveral lines of evidence support the anti-allergic effect of propolis and royal jelly. This effect involves inhibiting mast cell degranulation, suppressing cysteinyl-leukotriene release, as well as reducing serum histamine, IgG, and IgE levels in various allergic conditions by suppressing histamine H1 receptor [37,39,92]. Nevertheless, rare allergic reactions to bee products other than bee venom are documented in the literature. They are most frequent in small children [80,93]. Examples of such reactions comprise contact dermatitis in beekeepers following the handling of propolis, as well as contact stomatitis and oral mucositis after the usage of lozenges containing propolis [80]. Hence, bee products should be used with caution, especially in people with known allergies, pregnant and lactating women, and small children [61]. In addition, bee products can be safely consumed after adequate processing. Processing involves removal of known allergens such as enzyme treatment of royal jelly and filtration of bee venom by stepped-gradient open column [2,94]."}

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Apitherapy as a Possible Complementary Treatment for Sarcopenia\nRock paintings from the Stone Age portray consumption of bee products by humans [27]. The first evidence of human usage of bee products for therapeutic and cosmetic purposes dates back 6000 years in ancient Egypt and later in China, Greece, and Rome [27,28,29,30]. Current research interest is directed toward the use of natural substances, including bee products, as potential pharmaceuticals to modify disease progression [31]. The term “apitherapy” describes a category of complementary and alternative medicine that comprises therapeutic use of various bee products including apilarnil (atomized drone larva) to prevent and treat illnesses [30].\nBee workers of either Apis mellifera or Apis cerana species—the former is common in Europe, Asia, Africa, and America while the latter exists only in southern and southeastern Asia—produce and store multiple bioactive substances [32]. Royal jelly, propolis, bee pollen, honey, bee venom, bee bread, and bee wax are common products of the bee hive. They all (to a varying degree) possess multiple health promoting properties due to their high content of natural antioxidants such as flavonoids, phenols, or terpenoids [28,32]. Research documents variability in contents and effects of every single bee product, mainly due to the influence of bee species, botanical origin, geographic location, season, extraction, and handling procedures [2,28].\nSeveral lines of evidence describe anti-aging effects of royal jelly, bee pollen, and propolis both in humans and laboratory animals [2,33,34,35]. These three products are widely used as dietary supplements [36,37,38,39]. In the meantime, the literature gives examples of numerous dietary supplements that could successfully prevent or alleviate the progression of muscle mass loss in old age [40,41,42]. Bee products represent a part of this interventional strategy. However, the extent to which bee products can affect sarcopenia as well as understanding of their underlying mechanism of action are far from being clear. Therefore, we conducted this review with the aim of investigating the anti-aging properties of these products with a focus on skeletal muscle functioning in advanced age. In this respect, we reviewed animal and human studies investigating effects of the aforementioned products on skeletal muscle aging and elaborated on different mechanisms underlying these effects. Studies included in this review were retrieved by searching PubMed and Google scholar using a combination of terminologies of “sarcopenia, muscle wasting, muscle mass, lean body mass, skeletal muscle, motor” with “royal jelly, honey, bee pollen, propolis, bee venom, bee bread, bee wax, chrysin, apamin, caffeic acid phenethyl ester”. Snow ball manual search using reference lists of retrieved studies was also conducted. This search resulted in a number of studies, which addressed muscle wasting and related dynamics through the use of three bee products, namely royal jelly, bee pollen, and propolis. Figure 1, Panel A and Panel B, summarizes the chemical composition and biological properties of these bee products while this section elaborates on these products in depth.\n\n2.1. Royal Jelly: Its Constituents, Biological, and Pharmacological Activities\nRoyal jelly is a thick, milky, white-yellowish, acidic colloid substance secreted from the hypopharyngeal and mandibular salivary glands of young nurse honey bees (5–15 days old) [32,43]. In general, fresh royal jelly mostly consists of water (67% w/w) in addition to carbohydrates (16%), proteins and amino acids (12.5%), fat (5%), and many other elements [32]. However, royal jelly content of these substances noticeably varies depending on numerous factors like botanical source, bee species, bee artificial feeding, weather, season, location, method of processing, and the like [2,44].\nProtein is the most copious active element in royal jelly, representing half the weight of its dry matter [2]. It vastly comprises nine 49–87 kDa water-insoluble proteins, known as major royal jelly proteins 1–9 (MRJPs1-9) [2,45]. MRJPs constitute more than 80% of royal jelly protein content, and MRJPs1–5 constitute 82–90% of all MRJPs. MRJPs contain 400–578 amino acids that contribute to the antioxidant effect of royal jelly as well as its role in cell proliferation, cell adhesion, cell growth, and immunity [46,47]. Novel non-MRJPs proteins have been newly discovered [48]. Royalisin, jelleines, and aspimin are examples of other proteins that exist in royal jelly, albeit in small amounts. These proteins as well as MRJPs demonstrate strong antimicrobial and bactericidal activities even against the most drug-resistant bacterial strains such as methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, vancomycin-resistant Enterococci, as well as extended-spectrum β-lactamase-producing Proteus mirabilis and Escherichia coli [28,29].\nCarbohydrates (e.g., fructose, glucose maltose, trehalose, melibiose, ribose, and erlose) constitute 7.5–16% or royal jelly content [49]. Reducing sugars in royal jelly are thought to contribute to its epigenetic effect through the activation of insulin-like growth factor 1 (IGF-1) and mammalian target of rapamycin (mTOR) signaling cascades. Thus, they stimulate caste differentiation of Apis mellifera larvae into queens by increasing intake of food and key nutrients [50].\nLipids make up 7–18% of the dry weight of royal jelly. This fraction largely comprises a group of unique and rare saturated or monounsaturated short and medium chain fatty acids that are terminally or internally hydroxylated with terminal mono- or dicarboxylic acid functions [2,28]. The vast majority of royal jelly fat content (80–85%) consists of short hydroxyl fatty acids such as trans-10-hydroxy-2-decenoic acid (10-HDA), which exists only in royal jelly; and therefore, it is known as royal jelly acid or queen bee acid [28,49,51]. 10-HDA is one of the most potent bioactive elements in royal jelly expressing strong anti-aging, neuroprotective, antiproliferative, antimicrobial, antioxidant, anti-inflammatory, and epigenetic effects [52,53,54,55,56,57,58]. In addition, the lipid fraction of royal jelly contains phenolic acids (4–10%), wax (5–6%), steroids (3–4%), and phospholipids (0.4–0.8%) [49].\nA wide range of minor constituents and bioactive compounds exist profusely in royal jelly such as acetylcholine, nucleotides (adenosine, guanosine, adenosine tri-phosphate (ATP), adenosine monophosphate (AMP)), minerals (iron, sodium, calcium, potassium, zinc, magnesium, manganese, and copper), amino acids (8 out of 9 essential amino acids Val, Leu, Ile, Thr, Met, Phe, Lys, and Trp), vitamins (retinol (A), ascorbic acid (C), tocopherol (E), riboflavin (B2), niacin (B3), and other B vitamins), esters, aldehydes, ketones, alcohol, and minor heterocyclic compounds [2,28,49,59,60,61]. It is worth noting that royal jelly loses most of its bioactive ingredients and biological properties when stored at a temperature of 5 °C or higher. Therefore, freezing is the best method to store royal jelly [62]. Enzymatic treatment of royal jelly removes allergen proteins and enhances its nutrient content in addition to improving its digestibility and absorption in the gut without altering its freshness [2,59].\nRoyal jelly has been historically used as a beautifying agent by famous queens such as Cleopatra, and it is still involved in the cosmetic industry [29,56]. Its rich content of bioactive compounds grants it a plethora of diverse health benefits such as antioxidant, anti-inflammatory, neurotrophic, hypotensive, antidiabetic, antilipidemic, antirheumatic, anticarcinogenic, anti-fatigue, antiadipogenic, and antimicrobial activities [43,45,63]. Therefore, it is widely used to treat multiple serious conditions including diabetes, hypertension, hyperlipidemia, cancer, skin diseases, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease [2,43,46,59,64]. In addition, bee queens (which enjoy long lifespan as well as super fertility and physical qualities) consume royal jelly throughout their entire lives, and royal jelly is considered a promising anti-aging nutraceutical that can positively enhance fertility and improve body composition [2].\n\n2.2. Propolis: Its Constituents, Biological, and Pharmacological Activities\nPropolis, also known as bee glue, is a sticky wax-like substance that constitutes a mixture of bee salivary secretions, bee wax, and resinous sap occurring in the bark and leaf-buds of specific plants [37,65]. It comes in green, red, brown, or black colors based on the collected local flora [66]. The word propolis comprises two Greek words “pro” and “polis”, which in order mean “in front of or at the entrance to” and “community or city”. Propolis is a hive-defensive substance, which bees use to protect and repair their hives [67].\nPropolis is a unique product of a complex composition that comprises more than 420 chemical substances [37,68]. Nonetheless, its composition and biological activities vary considerably depending on its botanical and geographical origins as well as the time of harvesting [38,65,67]. Propolis is rich in oxyprenylated phenylpropanoids—secondary metabolites from plants, fungi, and bacteria [69]—such as 7-isopentenyloxucoumarin, boropinic acid, 4-geranyloxyferulic acid, and auraptene. The last two exist in raw Italian propolis at high concentrations: 107.12 and 145.37 μg/g of dry propolis, respectively. Flavonoids, a large group of phenolic compounds, are abundant in Italian propolis, and they are differentiated into several groups including flavanones (e.g., naringenine, 4.4 mg/g), flavones (e.g., apigenine, 1.7 mg/g), flavonols (e.g., galaning, 0.9 mg/g), tannins (e.g., gallic acid 8.4 mg/g), catechins (expressed as (+)-catechin 0.4 mg/g, and caffeic acid and its esters (expressed as caffeic acid, 9.2 mg/g) [69]. The most profuse flavonoids in ethanolic extracts of Brazilian propolis are artepillin C (38.6 mg/g), coumaric acid (10.6 mg/g), and kaempferide (12.6 mg/g) [70]. Key other constituents of propolis include polyphenol (e.g., phenolic acids and aromatic esters), phenolic aldehydes, terpenoids, ketones, enzymes (e.g., α- and β-amylase), vitamins (e.g., thiamin (B1), riboflavin (B2), pyridoxine (B6), ascorbic acid (C), tocopherol (E)), minerals (e.g., calcium, potassium, magnesium, iron, sodium, barium) essential oils, alcohol, fatty acids, β-steroids, and many other elements [37,38,67,68,71].\nThe attention of several drug targeting studies has recently been focused on the therapeutic activities of individual bioactive compounds in propolis [65,68]. Flavonoids comprise the majority of mostly studies bioactive substances in propolis. Chrysin (5,7-dihydroxyflavone) is a flavonoid that exists in certain mushrooms, flowers (e.g., blue passion flower), and in other bee products (e.g., honey). It expresses anti-inflammatory, antioxidant, anti-proliferative, and neuroprotective effects [72]. Caffeic acid phenethyl ester (CAPE), a derivative of hydroxycinnamic acid, expresses anti-oxidant, immunomodulatory, anti-inflammatory, antiviral, and ant-neoplastic properties [73,74,75]. Pinocembrin (5,7-dihydroxyflavanone) is the most copious flavonoid in propolis—1 g of balsam/an ethanolic extract from poplar propolis found in Spain contains up to 606–701 mg of pinocembrin [76]. It exists in numerous plants (e.g., Eucalyptus and Populus). It exhibits anti-inflammatory, antioxidant, antimicrobial, and antiproliferative activities [77,78].\nEssential/volatile oils are major bioactive constituents of propolis, and they contribute to its special aroma [79,80]. They also, partially, contribute to the strong antimicrobial, antioxidant, and anticancer activities of propolis [79,81,82]. The volatile fraction of propolis varies in each sample even within a single country due to plant source and climate [79]. For instance, cumulative knowledge shows that volatile oils in propolis found in countries surrounding the Mediterranean depend mainly on the botanical origin. They primarily comprise poplar-derived compounds (e.g., benzoic acid and its esters and oxygenated sesquiterpene β-eudesmol) and conifer-derived compounds such as the hydrocarbon monoterpene α-pinene [80]. Interestingly, the number of volatile compounds derived from a single type of propolis is also reported to vary according to extraction techniques. In this regard, reports from China show that traditional hydrodistillation, steam-distillation extraction, and dynamic headspace sampling could characterize around 12, 40 and 70 type of volatile components of propolis, respectively [79]. Moreover, the level of antimicrobial activity of volatile compounds of propolis greatly depends on their extent of purification [82].\nThanks to its countless bioactive elements, propolis enjoys a range of versatile biological and pharmacological properties including antimicrobial, antiviral, antifungal, antioxidant, anti-inflammatory, antineoplastic, antiaging, and cytostatic properties. In addition, it is considered a perfect natural food preservative due to its antimicrobial activity [35,38,65,66,68,71]. Because of its enormous health-promoting activities, propolis is widely used as a dietary supplement in many countries, especially in Japan [37,38,39].\nPropolis is not suitable for use in its crude state since it may contact harmful materials e.g., asphalt from the road [68]. Using solvents like ethanol, glycerol, chloroform, ether and acetone or water is necessary to get rid of hazardous substances and to increase its yield of bioactive compounds [67,68]. Although water may be a cheap solvent, propolis has poor solubility in water. Therefore, propolis water extracts are 10-fold lower in their phenolic contents than ethanol extracts. In addition, they retain the strong flavor and aroma of propolis [68]. Moreover, propolis contains allergenic components: caffeic acids derivates (e.g., 3-methyl-2-butenyl caffeate and phenylethyl caffeate), as well as benzyl salicylate and benzyl cinnamate [80]. Therefore, propolis use/consumption should be contraindicated in individuals with known allergies.\n\n2.3. Bee Pollen: Its Constituents, Biological, and Pharmacological Activities\nBee pollen is an api-material that originally comprises male gametophytes or spermatophytes of flowers, which stick to bee body. Bee workers mix these floral pollens with honey, nectar, and bee saliva. The latter is rich in various enzymes e.g., amylase, catalase, as well as lactic acid bacteria, which cause pollen fermentation [36,83,84]. Hence, the tiny wind pollen grains collected by bees aggregate together to form granules or pellets of 1.4–4 mm in size [84].\nIn addition to water, which in order constitutes 20–30% and 6–8% of the content of recently collected and dried bee pollen, bee pollen contains around 200 chemical compounds. Like other bee products, its composition varies considerably according to botanical origin. Carbohydrates account for the most abundant ingredient (18.50–84.25%), and reducing sugars such as glucose, fructose, and sucrose constitute the vastest majority (13–55%). Other major elements include proteins and essential amino acids (5–60%), unsaturated and saturated fatty acids (0.15–31.26%), crude fiber (0.3–20%), nucleic acids (especially RNA), and various minerals (e.g., potassium, phosphorus, calcium, magnesium, zinc, copper, manganese, and iron) [36,83,84,85,86]. In addition, its average total phenolic content is 30.59 mg gallic acid equivalents (GAE)/g, but again it varies considerably based on floral origin (0.69–213.20 mg GAE/g) [86]. Moreover, bee pollen is abundant in both water- and fat-soluble vitamins e.g., β-carotene (vitamin A precursor), ascorbic acid (C), tocopherol (E), folic acid (B9), and other vitamin B, especially niacin. Bee pollen contains other elements that still need to be explored (2–5%) [83]. Therefore, bee pollen represents a perfect whole health-promoting food. In fact, comparisons of the percentages of nutrients in bee pollen with daily required intake of an adult individual revealed that few grams of bee pollen can meet daily human nutritional requirements [83,84].\nBee pollen demonstrates various biological properties and therapeutic activities e.g., antioxidant, anti-inflammatory, anti-lipidemic, anticancer, antiallergic, and antimicrobial [36,87]. Existing knowledge emphasizes its antiaging effects: it reduced the production of age-related pigment known as lipofuscin (induced by oral peroxidized corn oil or intravenous alloxan injection) in cardiac muscle, brain, liver, and suprarenal gland in aged mice (reviewed in [34]).\nThe composition of bee pollens depends primarily on its botanical source since nutrient contents (e.g., polyphenols) of pollen grains, which support their survival and fusion with female gametes, vary between different plants [83,84]. Storage conditions are of great importance were it to retain its biological activities. Bee pollen should be consumed fresh soon after collection. Most of its major elements (reducing sugars, total proteins, vitamin C, and provitamin A) are destroyed at 40 °C. Lyophilization damages its vitamin content while freezing is recommended for the storage of bee pollen since it does not affect its chemical structure [83].\nDry pollen pellets resist decay due to their tough outer coat, which comprises two layers made of cellulose and sporopollenin [88,89]. However, ingestion of bee pollen by humans may not yield its optimal nutritional value because the hard sporopollenin shell hinders access of digestive secretions to the nutrient-rich core of the pellet. Biological, chemical, and mechanical techniques are used to break bee pollen microcapsules in order to enhance its digestibility in the gut. However, these methods may be expensive or ineffective i.e., they degrade important nutrients via enzymatic activity [88,90]. Ultraviolet spectroscopy and high performance liquid chromatography-photo diode array show that processing bee pollen through the use of an edible lipid-surfactant mixture (Captex 355 and Tween 80) increases its yield of polyphenols and flavonoid aglycones [90].\n\n2.4. Safety Profile of Royal Jelly, Propolis, and Bee Pollen\nPropolis exists in a plethora of commercial products that are directly consumed or used by humans e.g., lozenges, soap, toothpastes and mouth wash, creams, gels, cough syrups, wines, cakes, chewing gums, candies, shampoo, chocolate, skin lotions, processed meat, etc. [67]. In addition, royal jelly, bee pollen, and propolis are widely used as dietary supplements in many parts of the world [36,37,38,39]. Existing knowledge denotes no adverse effects from their consumption either in rodents or in humans [39,66]. The safety of pinocembrin, a flavonoid available in propolis and an approved drug in China, is documented since its elimination from the body is rapid [91]. The safety profile of bee pollen (both crude and processed) has been empirically tested. Oral consumption of bee pollen (up to 2 g/kg body weight) expressed no allergic reactions in mice including behavioral changes, salivation, diarrhea, respiratory or autonomic responses, restlessness, convulsions, tremors, or death [90]. In fact, the German Federal Board of Health acknowledges bee pollen as an official medicine [36].\nSeveral lines of evidence support the anti-allergic effect of propolis and royal jelly. This effect involves inhibiting mast cell degranulation, suppressing cysteinyl-leukotriene release, as well as reducing serum histamine, IgG, and IgE levels in various allergic conditions by suppressing histamine H1 receptor [37,39,92]. Nevertheless, rare allergic reactions to bee products other than bee venom are documented in the literature. They are most frequent in small children [80,93]. Examples of such reactions comprise contact dermatitis in beekeepers following the handling of propolis, as well as contact stomatitis and oral mucositis after the usage of lozenges containing propolis [80]. Hence, bee products should be used with caution, especially in people with known allergies, pregnant and lactating women, and small children [61]. In addition, bee products can be safely consumed after adequate processing. Processing involves removal of known allergens such as enzyme treatment of royal jelly and filtration of bee venom by stepped-gradient open column [2,94]."}

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Apitherapy as a Possible Complementary Treatment for Sarcopenia\nRock paintings from the Stone Age portray consumption of bee products by humans [27]. The first evidence of human usage of bee products for therapeutic and cosmetic purposes dates back 6000 years in ancient Egypt and later in China, Greece, and Rome [27,28,29,30]. Current research interest is directed toward the use of natural substances, including bee products, as potential pharmaceuticals to modify disease progression [31]. The term “apitherapy” describes a category of complementary and alternative medicine that comprises therapeutic use of various bee products including apilarnil (atomized drone larva) to prevent and treat illnesses [30].\nBee workers of either Apis mellifera or Apis cerana species—the former is common in Europe, Asia, Africa, and America while the latter exists only in southern and southeastern Asia—produce and store multiple bioactive substances [32]. Royal jelly, propolis, bee pollen, honey, bee venom, bee bread, and bee wax are common products of the bee hive. They all (to a varying degree) possess multiple health promoting properties due to their high content of natural antioxidants such as flavonoids, phenols, or terpenoids [28,32]. Research documents variability in contents and effects of every single bee product, mainly due to the influence of bee species, botanical origin, geographic location, season, extraction, and handling procedures [2,28].\nSeveral lines of evidence describe anti-aging effects of royal jelly, bee pollen, and propolis both in humans and laboratory animals [2,33,34,35]. These three products are widely used as dietary supplements [36,37,38,39]. In the meantime, the literature gives examples of numerous dietary supplements that could successfully prevent or alleviate the progression of muscle mass loss in old age [40,41,42]. Bee products represent a part of this interventional strategy. However, the extent to which bee products can affect sarcopenia as well as understanding of their underlying mechanism of action are far from being clear. Therefore, we conducted this review with the aim of investigating the anti-aging properties of these products with a focus on skeletal muscle functioning in advanced age. In this respect, we reviewed animal and human studies investigating effects of the aforementioned products on skeletal muscle aging and elaborated on different mechanisms underlying these effects. Studies included in this review were retrieved by searching PubMed and Google scholar using a combination of terminologies of “sarcopenia, muscle wasting, muscle mass, lean body mass, skeletal muscle, motor” with “royal jelly, honey, bee pollen, propolis, bee venom, bee bread, bee wax, chrysin, apamin, caffeic acid phenethyl ester”. Snow ball manual search using reference lists of retrieved studies was also conducted. This search resulted in a number of studies, which addressed muscle wasting and related dynamics through the use of three bee products, namely royal jelly, bee pollen, and propolis. Figure 1, Panel A and Panel B, summarizes the chemical composition and biological properties of these bee products while this section elaborates on these products in depth.\n\n2.1. Royal Jelly: Its Constituents, Biological, and Pharmacological Activities\nRoyal jelly is a thick, milky, white-yellowish, acidic colloid substance secreted from the hypopharyngeal and mandibular salivary glands of young nurse honey bees (5–15 days old) [32,43]. In general, fresh royal jelly mostly consists of water (67% w/w) in addition to carbohydrates (16%), proteins and amino acids (12.5%), fat (5%), and many other elements [32]. However, royal jelly content of these substances noticeably varies depending on numerous factors like botanical source, bee species, bee artificial feeding, weather, season, location, method of processing, and the like [2,44].\nProtein is the most copious active element in royal jelly, representing half the weight of its dry matter [2]. It vastly comprises nine 49–87 kDa water-insoluble proteins, known as major royal jelly proteins 1–9 (MRJPs1-9) [2,45]. MRJPs constitute more than 80% of royal jelly protein content, and MRJPs1–5 constitute 82–90% of all MRJPs. MRJPs contain 400–578 amino acids that contribute to the antioxidant effect of royal jelly as well as its role in cell proliferation, cell adhesion, cell growth, and immunity [46,47]. Novel non-MRJPs proteins have been newly discovered [48]. Royalisin, jelleines, and aspimin are examples of other proteins that exist in royal jelly, albeit in small amounts. These proteins as well as MRJPs demonstrate strong antimicrobial and bactericidal activities even against the most drug-resistant bacterial strains such as methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, vancomycin-resistant Enterococci, as well as extended-spectrum β-lactamase-producing Proteus mirabilis and Escherichia coli [28,29].\nCarbohydrates (e.g., fructose, glucose maltose, trehalose, melibiose, ribose, and erlose) constitute 7.5–16% or royal jelly content [49]. Reducing sugars in royal jelly are thought to contribute to its epigenetic effect through the activation of insulin-like growth factor 1 (IGF-1) and mammalian target of rapamycin (mTOR) signaling cascades. Thus, they stimulate caste differentiation of Apis mellifera larvae into queens by increasing intake of food and key nutrients [50].\nLipids make up 7–18% of the dry weight of royal jelly. This fraction largely comprises a group of unique and rare saturated or monounsaturated short and medium chain fatty acids that are terminally or internally hydroxylated with terminal mono- or dicarboxylic acid functions [2,28]. The vast majority of royal jelly fat content (80–85%) consists of short hydroxyl fatty acids such as trans-10-hydroxy-2-decenoic acid (10-HDA), which exists only in royal jelly; and therefore, it is known as royal jelly acid or queen bee acid [28,49,51]. 10-HDA is one of the most potent bioactive elements in royal jelly expressing strong anti-aging, neuroprotective, antiproliferative, antimicrobial, antioxidant, anti-inflammatory, and epigenetic effects [52,53,54,55,56,57,58]. In addition, the lipid fraction of royal jelly contains phenolic acids (4–10%), wax (5–6%), steroids (3–4%), and phospholipids (0.4–0.8%) [49].\nA wide range of minor constituents and bioactive compounds exist profusely in royal jelly such as acetylcholine, nucleotides (adenosine, guanosine, adenosine tri-phosphate (ATP), adenosine monophosphate (AMP)), minerals (iron, sodium, calcium, potassium, zinc, magnesium, manganese, and copper), amino acids (8 out of 9 essential amino acids Val, Leu, Ile, Thr, Met, Phe, Lys, and Trp), vitamins (retinol (A), ascorbic acid (C), tocopherol (E), riboflavin (B2), niacin (B3), and other B vitamins), esters, aldehydes, ketones, alcohol, and minor heterocyclic compounds [2,28,49,59,60,61]. It is worth noting that royal jelly loses most of its bioactive ingredients and biological properties when stored at a temperature of 5 °C or higher. Therefore, freezing is the best method to store royal jelly [62]. Enzymatic treatment of royal jelly removes allergen proteins and enhances its nutrient content in addition to improving its digestibility and absorption in the gut without altering its freshness [2,59].\nRoyal jelly has been historically used as a beautifying agent by famous queens such as Cleopatra, and it is still involved in the cosmetic industry [29,56]. Its rich content of bioactive compounds grants it a plethora of diverse health benefits such as antioxidant, anti-inflammatory, neurotrophic, hypotensive, antidiabetic, antilipidemic, antirheumatic, anticarcinogenic, anti-fatigue, antiadipogenic, and antimicrobial activities [43,45,63]. Therefore, it is widely used to treat multiple serious conditions including diabetes, hypertension, hyperlipidemia, cancer, skin diseases, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease [2,43,46,59,64]. In addition, bee queens (which enjoy long lifespan as well as super fertility and physical qualities) consume royal jelly throughout their entire lives, and royal jelly is considered a promising anti-aging nutraceutical that can positively enhance fertility and improve body composition [2].\n\n2.2. Propolis: Its Constituents, Biological, and Pharmacological Activities\nPropolis, also known as bee glue, is a sticky wax-like substance that constitutes a mixture of bee salivary secretions, bee wax, and resinous sap occurring in the bark and leaf-buds of specific plants [37,65]. It comes in green, red, brown, or black colors based on the collected local flora [66]. The word propolis comprises two Greek words “pro” and “polis”, which in order mean “in front of or at the entrance to” and “community or city”. Propolis is a hive-defensive substance, which bees use to protect and repair their hives [67].\nPropolis is a unique product of a complex composition that comprises more than 420 chemical substances [37,68]. Nonetheless, its composition and biological activities vary considerably depending on its botanical and geographical origins as well as the time of harvesting [38,65,67]. Propolis is rich in oxyprenylated phenylpropanoids—secondary metabolites from plants, fungi, and bacteria [69]—such as 7-isopentenyloxucoumarin, boropinic acid, 4-geranyloxyferulic acid, and auraptene. The last two exist in raw Italian propolis at high concentrations: 107.12 and 145.37 μg/g of dry propolis, respectively. Flavonoids, a large group of phenolic compounds, are abundant in Italian propolis, and they are differentiated into several groups including flavanones (e.g., naringenine, 4.4 mg/g), flavones (e.g., apigenine, 1.7 mg/g), flavonols (e.g., galaning, 0.9 mg/g), tannins (e.g., gallic acid 8.4 mg/g), catechins (expressed as (+)-catechin 0.4 mg/g, and caffeic acid and its esters (expressed as caffeic acid, 9.2 mg/g) [69]. The most profuse flavonoids in ethanolic extracts of Brazilian propolis are artepillin C (38.6 mg/g), coumaric acid (10.6 mg/g), and kaempferide (12.6 mg/g) [70]. Key other constituents of propolis include polyphenol (e.g., phenolic acids and aromatic esters), phenolic aldehydes, terpenoids, ketones, enzymes (e.g., α- and β-amylase), vitamins (e.g., thiamin (B1), riboflavin (B2), pyridoxine (B6), ascorbic acid (C), tocopherol (E)), minerals (e.g., calcium, potassium, magnesium, iron, sodium, barium) essential oils, alcohol, fatty acids, β-steroids, and many other elements [37,38,67,68,71].\nThe attention of several drug targeting studies has recently been focused on the therapeutic activities of individual bioactive compounds in propolis [65,68]. Flavonoids comprise the majority of mostly studies bioactive substances in propolis. Chrysin (5,7-dihydroxyflavone) is a flavonoid that exists in certain mushrooms, flowers (e.g., blue passion flower), and in other bee products (e.g., honey). It expresses anti-inflammatory, antioxidant, anti-proliferative, and neuroprotective effects [72]. Caffeic acid phenethyl ester (CAPE), a derivative of hydroxycinnamic acid, expresses anti-oxidant, immunomodulatory, anti-inflammatory, antiviral, and ant-neoplastic properties [73,74,75]. Pinocembrin (5,7-dihydroxyflavanone) is the most copious flavonoid in propolis—1 g of balsam/an ethanolic extract from poplar propolis found in Spain contains up to 606–701 mg of pinocembrin [76]. It exists in numerous plants (e.g., Eucalyptus and Populus). It exhibits anti-inflammatory, antioxidant, antimicrobial, and antiproliferative activities [77,78].\nEssential/volatile oils are major bioactive constituents of propolis, and they contribute to its special aroma [79,80]. They also, partially, contribute to the strong antimicrobial, antioxidant, and anticancer activities of propolis [79,81,82]. The volatile fraction of propolis varies in each sample even within a single country due to plant source and climate [79]. For instance, cumulative knowledge shows that volatile oils in propolis found in countries surrounding the Mediterranean depend mainly on the botanical origin. They primarily comprise poplar-derived compounds (e.g., benzoic acid and its esters and oxygenated sesquiterpene β-eudesmol) and conifer-derived compounds such as the hydrocarbon monoterpene α-pinene [80]. Interestingly, the number of volatile compounds derived from a single type of propolis is also reported to vary according to extraction techniques. In this regard, reports from China show that traditional hydrodistillation, steam-distillation extraction, and dynamic headspace sampling could characterize around 12, 40 and 70 type of volatile components of propolis, respectively [79]. Moreover, the level of antimicrobial activity of volatile compounds of propolis greatly depends on their extent of purification [82].\nThanks to its countless bioactive elements, propolis enjoys a range of versatile biological and pharmacological properties including antimicrobial, antiviral, antifungal, antioxidant, anti-inflammatory, antineoplastic, antiaging, and cytostatic properties. In addition, it is considered a perfect natural food preservative due to its antimicrobial activity [35,38,65,66,68,71]. Because of its enormous health-promoting activities, propolis is widely used as a dietary supplement in many countries, especially in Japan [37,38,39].\nPropolis is not suitable for use in its crude state since it may contact harmful materials e.g., asphalt from the road [68]. Using solvents like ethanol, glycerol, chloroform, ether and acetone or water is necessary to get rid of hazardous substances and to increase its yield of bioactive compounds [67,68]. Although water may be a cheap solvent, propolis has poor solubility in water. Therefore, propolis water extracts are 10-fold lower in their phenolic contents than ethanol extracts. In addition, they retain the strong flavor and aroma of propolis [68]. Moreover, propolis contains allergenic components: caffeic acids derivates (e.g., 3-methyl-2-butenyl caffeate and phenylethyl caffeate), as well as benzyl salicylate and benzyl cinnamate [80]. Therefore, propolis use/consumption should be contraindicated in individuals with known allergies.\n\n2.3. Bee Pollen: Its Constituents, Biological, and Pharmacological Activities\nBee pollen is an api-material that originally comprises male gametophytes or spermatophytes of flowers, which stick to bee body. Bee workers mix these floral pollens with honey, nectar, and bee saliva. The latter is rich in various enzymes e.g., amylase, catalase, as well as lactic acid bacteria, which cause pollen fermentation [36,83,84]. Hence, the tiny wind pollen grains collected by bees aggregate together to form granules or pellets of 1.4–4 mm in size [84].\nIn addition to water, which in order constitutes 20–30% and 6–8% of the content of recently collected and dried bee pollen, bee pollen contains around 200 chemical compounds. Like other bee products, its composition varies considerably according to botanical origin. Carbohydrates account for the most abundant ingredient (18.50–84.25%), and reducing sugars such as glucose, fructose, and sucrose constitute the vastest majority (13–55%). Other major elements include proteins and essential amino acids (5–60%), unsaturated and saturated fatty acids (0.15–31.26%), crude fiber (0.3–20%), nucleic acids (especially RNA), and various minerals (e.g., potassium, phosphorus, calcium, magnesium, zinc, copper, manganese, and iron) [36,83,84,85,86]. In addition, its average total phenolic content is 30.59 mg gallic acid equivalents (GAE)/g, but again it varies considerably based on floral origin (0.69–213.20 mg GAE/g) [86]. Moreover, bee pollen is abundant in both water- and fat-soluble vitamins e.g., β-carotene (vitamin A precursor), ascorbic acid (C), tocopherol (E), folic acid (B9), and other vitamin B, especially niacin. Bee pollen contains other elements that still need to be explored (2–5%) [83]. Therefore, bee pollen represents a perfect whole health-promoting food. In fact, comparisons of the percentages of nutrients in bee pollen with daily required intake of an adult individual revealed that few grams of bee pollen can meet daily human nutritional requirements [83,84].\nBee pollen demonstrates various biological properties and therapeutic activities e.g., antioxidant, anti-inflammatory, anti-lipidemic, anticancer, antiallergic, and antimicrobial [36,87]. Existing knowledge emphasizes its antiaging effects: it reduced the production of age-related pigment known as lipofuscin (induced by oral peroxidized corn oil or intravenous alloxan injection) in cardiac muscle, brain, liver, and suprarenal gland in aged mice (reviewed in [34]).\nThe composition of bee pollens depends primarily on its botanical source since nutrient contents (e.g., polyphenols) of pollen grains, which support their survival and fusion with female gametes, vary between different plants [83,84]. Storage conditions are of great importance were it to retain its biological activities. Bee pollen should be consumed fresh soon after collection. Most of its major elements (reducing sugars, total proteins, vitamin C, and provitamin A) are destroyed at 40 °C. Lyophilization damages its vitamin content while freezing is recommended for the storage of bee pollen since it does not affect its chemical structure [83].\nDry pollen pellets resist decay due to their tough outer coat, which comprises two layers made of cellulose and sporopollenin [88,89]. However, ingestion of bee pollen by humans may not yield its optimal nutritional value because the hard sporopollenin shell hinders access of digestive secretions to the nutrient-rich core of the pellet. Biological, chemical, and mechanical techniques are used to break bee pollen microcapsules in order to enhance its digestibility in the gut. However, these methods may be expensive or ineffective i.e., they degrade important nutrients via enzymatic activity [88,90]. Ultraviolet spectroscopy and high performance liquid chromatography-photo diode array show that processing bee pollen through the use of an edible lipid-surfactant mixture (Captex 355 and Tween 80) increases its yield of polyphenols and flavonoid aglycones [90].\n\n2.4. Safety Profile of Royal Jelly, Propolis, and Bee Pollen\nPropolis exists in a plethora of commercial products that are directly consumed or used by humans e.g., lozenges, soap, toothpastes and mouth wash, creams, gels, cough syrups, wines, cakes, chewing gums, candies, shampoo, chocolate, skin lotions, processed meat, etc. [67]. In addition, royal jelly, bee pollen, and propolis are widely used as dietary supplements in many parts of the world [36,37,38,39]. Existing knowledge denotes no adverse effects from their consumption either in rodents or in humans [39,66]. The safety of pinocembrin, a flavonoid available in propolis and an approved drug in China, is documented since its elimination from the body is rapid [91]. The safety profile of bee pollen (both crude and processed) has been empirically tested. Oral consumption of bee pollen (up to 2 g/kg body weight) expressed no allergic reactions in mice including behavioral changes, salivation, diarrhea, respiratory or autonomic responses, restlessness, convulsions, tremors, or death [90]. In fact, the German Federal Board of Health acknowledges bee pollen as an official medicine [36].\nSeveral lines of evidence support the anti-allergic effect of propolis and royal jelly. This effect involves inhibiting mast cell degranulation, suppressing cysteinyl-leukotriene release, as well as reducing serum histamine, IgG, and IgE levels in various allergic conditions by suppressing histamine H1 receptor [37,39,92]. Nevertheless, rare allergic reactions to bee products other than bee venom are documented in the literature. They are most frequent in small children [80,93]. Examples of such reactions comprise contact dermatitis in beekeepers following the handling of propolis, as well as contact stomatitis and oral mucositis after the usage of lozenges containing propolis [80]. Hence, bee products should be used with caution, especially in people with known allergies, pregnant and lactating women, and small children [61]. In addition, bee products can be safely consumed after adequate processing. Processing involves removal of known allergens such as enzyme treatment of royal jelly and filtration of bee venom by stepped-gradient open column [2,94]."}