International Journal of Molecular Sciences Review Royal Jelly and Its Components Promote Healthy Aging and Longevity: From Animal Models to Humans Hiroshi Kunugi 1 and Amira Mohammed Ali 1,2,* 1 Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan; [email protected] 2 Department of Psychiatric Nursing and Mental Health, Faculty of Nursing, Alexandria University, Alexandria 21527, Egypt * Correspondence: [email protected]; Tel.: +81-042-346-1714 Received: 3 September 2019; Accepted: 18 September 2019; Published: 20 September 2019 Abstract: Aging is a natural phenomenon that occurs in all living organisms. In humans, aging is associated with lowered overall functioning and increased mortality out of the risk for various age-related diseases. Hence, researchers are pushed to find effective natural interventions that can promote healthy aging and extend lifespan. Royal jelly (RJ) is a natural product that is fed to bee queens throughout their entire life. Thanks to RJ, bee queens enjoy an excellent reproductive function and lengthened lifespan compared with bee workers, despite the fact that they have the same genome. This review aimed to investigate the effect of RJ and/or its components on lifespan/healthspan in various species by evaluating the most relevant studies. Moreover, we briefly discussed the positive effects of RJ on health maintenance and age-related disorders in humans. Whenever possible, we explored the metabolic, molecular, and cellular mechanisms through which RJ can modulate age-related mechanisms to extend lifespan. RJ and its ingredients—proteins and their derivatives e.g., royalactin; lipids e.g., 10-hydroxydecenoic acid; and vitamins e.g., pantothenic acid—improved healthspan and extended lifespan in worker honeybees Apis mellifera, Drosophila Melanogaster flies, Gryllus bimaculatus crickets, silkworms, Caenorhabditis elegans nematodes, and mice. The longevity effect was attained via various mechanisms: downregulation of insulin-like growth factors and targeting of rapamycin, upregulation of the epidermal growth factor signaling, dietary restriction, and enhancement of antioxidative capacity. RJ and its protein and lipid ingredients have the potential to extend lifespan in various creatures and prevent senescence of human tissues in cell cultures. These findings pave the way to inventing specific RJ anti-aging drugs. However, much work is needed to understand the effect of RJ interactions with microbiome, diet, activity level, gender, and other genetic variation factors that affect healthspan and longevity. Keywords: aging; alternative therapy; composition of royal jelly; dietary interventions; healthspan; lifespan; longevity; royal jelly; IGF-1; oxidative stress 1. Introduction Reduced mortality from both communicable and noncommunicable diseases accelerates the growth of aging populations worldwide. However, long living entails reduced healthspan out of increased burden of noncommunicable diseases [1]. Aging, healthspan, and lifespan are tightly related concepts. Though aging is a natural phenomenon, numerous factors such as stress, poor nutrition, and pollution are associated with increased internal production of free radicals, which enhance chronic subclinical inflammation and lead to faster aging [2,3]. Aging-related oxidative damage and Int. J. Mol. Sci. 2019, 20, 4662; doi:10.3390/ijms20194662 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 4662 2 of 26 Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 27 inflammationdamage and contributeinflammation to a trailcontribute of cellular to a and trail molecular of cellular alterations: and molecular telomere alterations: attrition, epigenetic telomere alterations,attrition, epigenetic genome alterations, instability, genome reduced instability, proteostasis, reduced disturbed proteostasis, nutrient disturbed sensing, nutrient mitochondrial sensing, dysfunction,mitochondrial cellular dysfunction, senescence, cellular stem cellsenescence, exhaustion, stem and cell altered exhaustion, intercellular and communication. altered intercellular In this respect,communication. aging represents In this respect, a process aging of random represents cellular a process degradation of random [4–6 ],cellular which degradation is associated [4–6], with increasedwhich is associated likelihood with of progressive increased likelihood loss of function, of progressive decreased loss fertility, of function, and increased decreased risk fertility, of various and diseasesincreased (both risk physicalof various and diseases cognitive)—contributing (both physical and to cognitive)—contributing premature death and increased to premature morbidity death in agingand increased populations morbidity (Figure in1)[ aging2,7]. populations (Figure 1) [2,7]. FigureFigure 1.1. TheThe dynamicsdynamics ofof aging-relatedaging-related decreasedecrease ofof healthspanhealthspan andand lifespan.lifespan. TheThe productionproduction ofof freefree radicalsradicals increasesincreases withwith agingaging (which(which isis onon thethe riserise outout ofof improvedimproved diseasedisease management)management) andand alsoalso withwith exposureexposure toto variousvarious stressesstresses (e.g.,(e.g., pollution,pollution, poorpoor nutrition,nutrition, andand psychologicalpsychological stress)stress) leadingleading toto oxidativeoxidative stress. This is is associated associated with with reduced reduced pr productionoduction of of antioxidant antioxidant enzymes enzymes and and activation activation of ofinflammatory inflammatory pathways. pathways. Both Both oxidative oxidative stress stress and and chronic chronic inflammation inflammation lead lead to a totrail a trail of cellular of cellular and andmolecular molecular alterations: alterations: telomere telomere attrition, attrition, epigenetic epigenetic alterations, alterations, genome genome instability, instability, reducedreduced proteostasis,proteostasis, disturbeddisturbed nutrientnutrient sensing,sensing, mitochondrialmitochondrial dysfunction,dysfunction, cellularcellular senescence,senescence, stemstem cellcell exhaustion,exhaustion, and and altered altered intercellular intercellular communication. communication. Such Such age-related age-related physiological physiological alterations alterations result result in poorin poor health health and loss and of functionloss of outfunction of increased out of occurrence increased of variousoccurrence metabolic of various and neurodegenerative metabolic and disorders.neurodegenerative Age-related disorders. disorders Age-related are associated disorder withs increasedare associated mortality with andincreased premature mortality death and i.e., decreasedpremature lifespan. death i.e., decreased lifespan. A recent review indicates that family profiles of centenarians emphasize the contribution of A recent review indicates that family profiles of centenarians emphasize the contribution of “protective or longevity genes” to extreme longevity as well as to low incidence of age-related “protective or longevity genes” to extreme longevity as well as to low incidence of age-related diseases in this group [5]. Apart from genetic factors, favorable environmental conditions and diseases in this group [5]. Apart from genetic factors, favorable environmental conditions and healthy healthy lifestyles contribute to low morbidity in people who survive to extreme ages [8,9]. Therefore, lifestyles contribute to low morbidity in people who survive to extreme ages [8,9]. Therefore, the the worldwide substantial increase of aging populations, who encounter a trail of debilitating illnesses, worldwide substantial increase of aging populations, who encounter a trail of debilitating illnesses, has driven researchers to find strategies to slow aging and support a healthy lifespan by delaying has driven researchers to find strategies to slow aging and support a healthy lifespan by delaying the the onset of age-related diseases [5]. Research denotes that the natural decline of function that onset of age-related diseases [5]. Research denotes that the natural decline of function that occurs occurs with aging, as well as age-related disorders, can be prevented and/or reversed through with aging, as well as age-related disorders, can be prevented and/or reversed through environmental modifications such as dietary interventions [10,11]. Accumulating evidence indicates environmental modifications such as dietary interventions [10,11]. Accumulating evidence indicates that functional foods can promote healthy aging, reduce morbidity, and lengthen healthy lifespans [12]. that functional foods can promote healthy aging, reduce morbidity, and lengthen healthy lifespans Royal jelly (RJ) is considered a functional food (with a documented safety profile) because it has [12]. Royal jelly (RJ) is considered a functional food (with a documented safety profile) because it has a range of pharmacological activities: antioxidant, anti-inflammatory, antitumor, antimicrobial, a range of pharmacological activities: antioxidant, anti-inflammatory, antitumor, antimicrobial, anti- anti-hypercholesterolemic, vasodilative, and hypotensive. Indeed, RJ has been widely used to treat hypercholesterolemic, vasodilative, and hypotensive. Indeed, RJ has been widely used to treat several several health conditions such as diabetes mellitus, cardiovascular diseases, and cancer, to name a health conditions such as diabetes mellitus, cardiovascular diseases, and