**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 inflammation contribute to a trail of cellular and molecular alterations: telomere attrition, epigenetic

alterations, genome instability, reduced proteostasis, disturbed nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. In this respect, aging represents a process of random cellular degradation [4–6], which is associated with increased likelihood of progressive loss of function, decreased fertility, and increased risk of various diseases (both physical and cognitive)—contributing to premature death and increased morbidity in aging populations (Figure 1) [2,7].

**Figure 1.** The dynamics of aging-related decrease of healthspan and lifespan. The production of free radicals increases with aging (which is on the rise out of improved disease management) and also with exposure to various stresses (e.g., pollution, poor nutrition, and psychological stress) leading to oxidative stress. This is associated with reduced production of antioxidant enzymes and activation of inflammatory pathways. Both oxidative stress and chronic inflammation lead to a trail of cellular and molecular alterations: telomere attrition, epigenetic alterations, genome instability, reduced proteostasis, disturbed nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Such age-related physiological alterations result in poor health and loss of function out of increased occurrence of various metabolic and neurodegenerative disorders. Age-related disorders are associated with increased mortality and premature death i.e., decreased lifespan.

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 diseases in this group [5]. Apart from genetic factors, favorable environmental conditions and healthy lifestyles contribute to low morbidity in people who survive to extreme ages [8,9]. Therefore, the 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 the onset of age-related diseases [5]. Research denotes that the natural decline of function that occurs 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 that functional foods can promote healthy aging, reduce morbidity, and lengthen healthy lifespans [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, anti-hypercholesterolemic, vasodilative, and hypotensive. Indeed, RJ has been widely used to treat several health conditions such as diabetes mellitus, cardiovascular diseases, and cancer, to name a few [13,14].

RJ is a creamy substance secreted from the mandibular and hypopharyngeal glands of the worker honeybee *Apis mellifera*. It is the food of all bee larvae during their first 3 days of life; workers then shift to worker jelly (WJ), composed mainly of honey and pollen, while bee queens continue to consume RJ [15–17]. It is suggested that RJ is a potent promoter of healthy aging and longevity because it enhances overall health and fertility of queen bees, who may lay up to 3000 eggs a day and survive as long as five years compared with infertile workers that live up to 45 days only [18–20]. However, studies of the effect RJ on longevity in humans are scarce, presumably due to technical and ethical reasons. In this respect, this paper reviews, synthesizes, and discusses the most relevant studies that used RJ to enhance healthspan and extend lifespan in different species. We also examined the metabolic, molecular, and cellular mechanisms associated with the longevity-promoting properties of RJ.
