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The Role of Ghrelin and Ghrelin Signaling in Aging

Education Center for Doctors in Remote Islands and Rural Areas, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima 890-8544, Japan
Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2017, 18(7), 1511;
Submission received: 22 June 2017 / Revised: 4 July 2017 / Accepted: 7 July 2017 / Published: 12 July 2017
(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)


With our aging society, more people hope for a long and healthy life. In recent years, researchers have focused on healthy longevity factors. In particular, calorie restriction delays aging, reduces mortality, and extends life. Ghrelin, which is secreted during fasting, is well known as an orexigenic peptide. Because ghrelin is increased by caloric restriction, ghrelin may play an important role in the mechanism of longevity mediated by calorie restriction. In this review, we will discuss the role of orexigenic peptides with a particular focus on ghrelin. We conclude that the ghrelin-growth hormone secretagogue-R signaling pathway may play an important role in the anti-aging mechanism.

1. Introduction

As people age, the risk for aging-related diseases including cancer, cardiovascular disease, and neurodegenerative disease also increases. People desire both a long and healthy life span. The life span of humans has increased in conjunction with the development of modern medicine. The development of a medication to control and suppress aging is in demand [1].
According to Herskind in Denmark, hereditary factors only contribute around 20–30% to a person’s life expectancy [2]. Centenarians, those who live to or beyond the age of 100 years, are thought to have a higher hereditary contribution than non-centenarians [3]. According to a United Nations report in 2015, the number of centenarians in the world has surpassed 450,000 people, four times more than in 1990 [4]. Although the number of centenarians is increasing every year, only a few people have lived longer than 115 years of age. In other words, the average life expectancy of humans has increased, but the maximum life span has not.
During the aging process, most organisms including humans will experience a decrease in physiological and psychological functions. Mechanisms of aging have been proposed, but many details are unknown.
Ghrelin, a 28-amino acid peptide, is the endogenous ligand for growth hormone secretagogue (GHS) and is a main regulator of GH secretion. Ghrelin appears to be involved in several physiological and pathophysiological mechanisms in humans, including aging [5,6]. The known biological activities associated with ghrelin continue to expand. Thus, in this review, we will discuss aging, with a particular focus on its relationship with ghrelin.

2. Aging and Longevity

2.1. Evolution and Aging

Aging is caused by malfunctions due to irreversible physiological processes, including the accumulation of damage in the living body. Many scientists have used nematodes (Caenorhabditis elegans (C. elegans)) and yeast (Saccharomyces cerevisiae) to explore the aging process. Both of these species have a short life span that leads to easier genetic analysis. In the 1980s, Friedman and Johnson discovered a gene in C. elegans called age-1, which controls senescence and is related to aging. The study showed that mutations in age-1 improve the longevity of C. elegans [7]. Age-1 encodes the nematode homolog of phosphatidylinositol 3-kinase (PI3K) and transmits an insulin-like signal [8], which inhibits nuclear transport of the nematode homolog of DAF-16, a member of the forkhead box O (FOXO) family of transcription factors. DAF-16 is activated via a decrease in the insulin-like signal, and modulates a gene cluster that is necessary to control aging [9]. Moreover, scientists have also revealed that both the target of rapamycin (TOR) pathway [10] and the silent information regulator 2 pathway are important for controlling life span [11]. These life span control-signaling pathways are an essential part of longevity control and are also conserved in mammals.

2.2. Calories and Longevity

In 1935, McCay first reported the effect of caloric restriction (CR) on life span in rats [12]. CR has been utilized as the most effective experimental method for investigation of the mechanism of aging in geriatrics. Many studies have shown that CR delays most aging-related physiological processes in a variety of species, including mammals and also prevents many aging-related diseases [13]. A long-term study in rhesus monkeys showed that CR extends life span and delays the onset of several pathologic diseases, such as diabetes, cancer, cardiovascular disease, and brain atrophy [14,15]. Many studies have shown that CR decreases oxidative stress, which is thought to be the main mechanism of the aging process [16]. The other mechanisms by which CR controls aging are related to signaling pathways including the Sirtuin (Sir2), insulin-like growth factor 1 (IGF-1), and TOR pathways [17]. Sirtuin is controlled by nicotinamide adenine dinucleotide (NAD), which mediates metabolism. The insulin-like signal is controlled by glucose, and the TOR signal is controlled by amino acids and ATP. In young rats, CR decreases GH secretion and the plasma GH concentration [18].
A clinical study of persons 100 years old or older in Okinawa suggested that CR leads to longevity and well-being [19]. Since the first evidence that CR extends life span and suppresses age-related chronic diseases was presented, numerous studies have also reported the relationship between body weight and mortality. Being overweight is associated with an increased risk of total mortality compared with being of normal weight [20].
Diet-induced obesity causes ghrelin resistance, which is improved by weight loss due to CR [21]. After 24 months, mood also clearly improved in the group with CR compared with a free feeding group. CR reduces tension and improves general health and sex drive [22]. Ghrelin resistance also occurs in elderly persons [23].

2.3. IGF-1 and Other Age-Related Factors

2.3.1. GH and IGF-1

Human aging is related to a change in GH/IGF-1 activity. The IGF-1 receptor is encoded by daf-2 [24]. Age-1 and a daf-2 variant in the nematode result in a life span that is 2–3 times longer than that of the wild type. Age-1 transmits an insulin-like signal [8]. Daf-2 has homology with an insulin receptor gene in the human genome and the IGF-1 receptor gene. [25]. A similar result was seen in yeast and Drosophila, in which life span is extended in a genetic variant with functional deletion of a component of the insulin/IGF-1-like signaling pathway [26,27]. In addition, CR also reduces the plasma IGF-1 concentration [28].
Circulating levels of GH, IGF-1, and ghrelin decline with aging, and aging may impair endogenous ghrelin signaling. Aging is characterized by a decrease in somatotroph cell functionality involving GH-releasing hormone receptor. Many studies have suggested that GH is a key factor in aging. The age-related decline in the activity of the GH/IGF-I axis is considered to contribute to age-related changes.
The efficacy of GH and/or ghrelin therapy in animal models and clinical studies has been reported. Administration of human GH for six months was accompanied by an 8.8% increase in lean body mass, a 14.4% decrease in adipose-tissue mass, and a 1.6% increase in average lumbar vertebral bone density [29]. Another study indicated the effect of combined therapy with ghrelin and GH for repair of organ injury and survival and improved immune function in septic aged animals [30]. GH levels increase when a physically unimpaired person is given the ghrelin agonist, anamorelin 25 mg orally, although the increase is minimal in young males and females compared with elderly males and females [23].
Although anti-aging effects of GH have been reported, the risk of the use of GH in healthy persons is still unknown. Whether or not GH deficiency constitutes a beneficial adaptation to aging or can serve as an anti-aging therapy is unclear [29,31], despite an article showing that continued GH therapy leads to unacceptable side effects. GH therapy in healthy elderly persons has not been thoroughly explored, but data suggest that GH treatment is associated with small changes in body composition and increased rates of adverse events. Thus, GH cannot be recommended as an anti-aging therapy [32]. In addition, in 2009, the Growth Hormone Research Society presented conclusions regarding the use of GH and GHS for promoting life span. They stated that until future carefully designed, long-term clinical studies with validated outcome parameters have been conducted, the clinical use of GH or GHS in older adults, alone or in combination with testosterone, cannot be recommended [33].

2.3.2. Sirtuin

Sir2, a NAD-dependent histone deacetylase, controls the life of the mother cell of the yeast fungus. In experimental models, a variant with inactivated Sir2 is short-lived, and a variant that overexpresses Sir2 has a longer life span than the wild type [34]. Sir2 also controls the life span in individual nematodes and Drosophila [35,36]. In Sir2 knockout models of yeast fungus, nematodes, and Drosophila, the life extension effect of CR is inhibited [36,37]. The Sir2 homolog in mammals is called Sirtuin 1 (Sirt1). Sirt1 is associated with various effects of CR, including an increase in life span. Sirt1 may affect neuropeptide Y (NPY)/agouti-related protein (AgRP)-positive neurons and metabolism. Sirt1 deacetylates other important proteins such as histones, p53, NF-κB, FOXO, and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) [38]. In transgenic mice that overexpress Sirt1, glucose tolerance is high, and a healthy metabolic state is present, similar to what is seen in calorie-restricted mice [39]. The hypothalamic melanocortin system is affected by Sirt1, which promotes the activity and connectivity of this system, resulting in a negative energy balance. On the other hand, in Sirt1 knockout mice, life extension due to CR is not seen [40]. Sirt1 is necessary to control energy balance related to aging and longevity, and plays an important role in the normal response to CR [41,42,43]. In an animal model, inhibition of brain Sirt1 activity decreases AgRP neuronal activity and inhibits proopiomelanocortin (POMC)-positive neurons. A Sirt1 inhibitor decreases food intake via melanocortin receptors, and the melanocortin 4 receptor (MC4R) antagonist reverses the effect of Sirt1 on food intake. This activity of Sirt1 is related to the mitochondrial protein, UCP2. In addition, knockout of Sirt1 in hypothalamic AgRP neurons decreases the electric responses of AgRP neurons to ghrelin and decreases food intake, leading to decreased lean mass, fat mass, and body weight [44].

2.3.3. Klotho

Klotho is expressed mainly in the kidney, parathyroid gland, and brain [45]. Overexpression of Klotho extends life span, and inhibition of Klotho promotes aging. Klotho-deficient mice (kl−/−) present with symptoms similar to aging, including growth retardation, hypogonadotropic hypogonadism, skin atrophy, sarcopenia, vascular calcification, osteopenia, cognitive impairment, pulmonary emphysema, and death at approximately two months of age [46,47,48]. Klotho reduces oxidative stress through phosphate metabolism [47]. In addition, Klotho plays an important role in the bone-kidney endocrine axis and acts on fibroblast growth factor-23 [49]. The increased mortality in overweight individuals may be correlated with the level of Klotho gene expression in these people [50].

2.3.4. TOR

TOR is a serine-threonine kinase that is highly expressed in yeast, plants, nematodes, flies, mice, and humans [51]. TOR is the catalytic subunit of two protein complexes, TORC1 (TOR complex 1) and TORC2 (TOR complex 2). The differences between these two complexes are in their protein structures, rapamycin sensitivity, activated signal of upper reach, and downstream output. TOR unifies various intracellular environmental factors such as insulin and other growth factors, the energy state, and the oxidation-reduction state. TOR also controls growth, survival, and proliferation of the cell through transcription and translation [52,53,54]. In nematodes, knockout of TOR and Raptor (TORC1 subunit) leads to life span extension [10,55]. Life span is thought to be extended by mimicking the effect of CR. Life span is also extended by knockdown of S6 kinase, which is one of the targets of TOR [56]. CR increases the number of intestinal stem cells through mTOR1 (mammalian TOR 1) and Sirt1. Thus, rapamycin, which is an mTOR1 inhibitor, may block the action of CR in intestinal stem cells [57].

3. Ghrelin and Aging

3.1. Ghrelin and NPY

The hypothalamus plays an important role in aging. In the hypothalamus, complex neural networks regulate homeostasis including appetite control. Many factors are implicated in the hypothalamic regulation of food intake, including melanin-concentrating hormone, NPY, AgRP, POMC, and cocaine- and amphetamine-regulated transcript. Ghrelin is a peripheral hormone with orexigenic properties and is part of a regulatory feedback loop between the periphery and brain. Among the numerous circulating appetite-regulating peptides, these two orexigenic peptides, NPY and ghrelin, are important factors in aging [58].
One hypothesis states that aging is associated with attenuated ghrelin signaling. CR produces health benefits accompanied by enhanced ghrelin production. Ghrelin is present in two forms: unacylated ghrelin; des-acyl ghrelin and acylated ghrelin; acyl ghrelin. CR increases plasma acyl ghrelin and des-acyl ghrelin concentrations in an animal model [59]. In addition, CR increases expression of hypothalamic AgRP and NPY, in contrast to reduced expression of POMC [60].
Recently, scientists have focused on the effect of NPY and ghrelin in autophagy in cortical neurons and their involvement in CR-induced autophagy. CR stimulates autophagy and increases NPY and ghrelin at the same time. NPY, an orexigenic peptide, decreases with aging. One of the causes of aging is impaired autophagy. CR mimetic cell culture medium stimulates autophagy. Ghrelin promotes autophagy via NPY in the hypothalamus, and exogenous NPY or ghrelin stimulates autophagy. On the other hand, NPY or ghrelin receptor antagonists block this effect. Impaired autophagy occurs in aging and age-related neurodegenerative diseases, and NPY and ghrelin mediate the neuroprotective effects induced by CR [61].
Long-term CR also mediates NPY receptor subtype density in rats. NPY and ghrelin may participate in autophagy adjustment through NPY Y1 and Y5 receptors in the hypothalamus [61,62,63,64]. The life span of mice is extended when they are fed with 70% of free food intake. However, the life span is not extended in similarly fed NPY knockout mice [65]. Oxidative stress tolerance and the tumor suppressant effect of CR are also attenuated in NPY knockout mice.
Ghrelin is secreted from the stomach during fasting [66] and has various physiologic functions in addition to its role as an orexigenic hormone. In the hypothalamus, ghrelin promotes expression of AgRP and NPY. Ghrelin stimulates GH secretion [67], gastrointestinal movement [68], and heart systole [69]. Ghrelin also controls energy metabolism [66], insulin secretion [70,71], inflammation [72], apoptosis, cardiovascular function, immune function, and neurodegeneration [73]. Ghrelin stimulates secretion of GH through growth hormone secretagogue receptor (GHS-R). Two isoforms, GHS-R1a and GHS-R1b, have been identified. GHS-R1a binds acyl ghrelin and transduces its message to induce GH secretion and stimulate secretion of IGF-1 from the liver. GHS-R1a is expressed widely in the pituitary, hypothalamus, pancreas, adipose tissue, immune cells, and the cardiac system. Thus, GHS-R1a agonists or antagonists may serve as novel and effective therapeutic options for many syndromes and diseases, such as cancer cachexia, aging-related cognitive decline, obesity, and diabetes [74].
The orexigenic effect of ghrelin due to CR is caused by activation of adenosine monophosphate-activated protein kinase (AMPK) in NPY neurons in the hypothalamus arcuate nucleus. Ghrelin activates AMPK, which increases NAD+ and stimulates Sirt1 activity. Ghrelin secretion due to CR is neuroprotective of dopaminergic neurons [75].
Several studies have suggested that age and obesity decrease the circulating acyl ghrelin levels [75,76,77]. Ablation of ghrelin signaling inhibits liver steatosis, which is related to reduce peroxisome proliferator-activated receptor (Ppar)-γ expression and enhanced insulin receptor substrate 2 (Irs2) expression. This study indicated that the effect of CR depends on enhanced metabolic flexibility independent of endogenous ghrelin or des-acyl ghrelin signaling [76].
In the absence of melanocortin-3 receptors, lower AgRP/NPY expression, attenuated food anticipatory activity could enhance circuitry regulating anticipatory responses to nutrient loading were seen, which suggest the importance of melanocortin-3 receptors as modulators of anticipatory responses to feeding [77]. Ghrelin signaling is an important thermogenic regulator in aging. During aging, plasma ghrelin and GHS-R expression in brown adipose tissue are increased. Increased plasma ghrelin during aging may lead to an imbalance in thermogenic regulation, which may in turn exacerbate impaired thermogenic regulation in aging [78]. AgRP neurons are key sites for GHS-R-mediated thermogenesis, and GHS-R in AgRP neurons play crucial roles in governing energy utilization and pathogenesis of diet-induced obesity [79].
Ghrelin might be a target for potential anti-obesity therapies. In obese patients, ghrelin levels were negatively associated with fasting insulin and HOMA-IR [80]. Leptin has been implicated as the antagonist in leptin and ghrelin systems. Leptin induces inhibition of AgRP and NPY expression, which is opposite to the effect of ghrelin [81]. Recessive mutations of the ob gene lead to accelerate morbid obesity and metabolic disorders, resulting in early mortality and a shortened life span. Obese ob/ob mice with enhanced leptin transgenic expression show a life span that is more than double that of control obese ob/ob mice, which have a life span similar to that of normal wild-type mice [82]. However, ob/ob mice fed a high fat diet (HFD) remain sensitive to ghrelin, which indicated that hyperleptinaemia, instead of obesity or a HFD, causes ghrelin resistance [83]. The life-extending benefits of leptin are associated with drastic reductions in visceral fat, blood glucose, and insulin levels, but elevated ghrelin levels. Thus, leptin derived from ectopic gene expression in the hypothalamus alone is both necessary and sufficient to normalize the life span.
An investigation of age-related metabolic changes showed that plasma acyl ghrelin levels are lower in young mice, whereas leptin levels under normal feeding conditions are substantially higher in old mice. The expression levels of hypothalamic preproghrelin under normal feeding conditions and the expression levels of NPY and AgRP under fasting conditions are lower compared with those of young mice [84].
Another study has investigated clinical biomarkers that distinguish between long-lived and short-lived individuals [85]. Compared with “long-lived” participants (older than 90 years), no significant single biomarker, including ghrelin, insulin, leptin, interleukin-6, adiponectin, or testosterone, was found in “short-lived” participants (72–76 years of age) [85]. Ghrelin or leptin may not be an effective single biomarker of health, and a combination of multiple biomarkers is likely needed.
Recently, the physiological function of butyrylcholinesterase (BChE) as a ghrelin hydrolase has been reported [86]. BChE converts acyl ghrelin into des-acyl ghrelin. High levels of BChE predict long-term survival of patients with coronary artery disease [87]. BChE regulates ghrelin and affects emotional behavior and life span in relation to ghrelin [88]. Overexpression of BchE induces low ghrelin levels and reduced aggression and social stress in mice [88]. One hypothesis is that elderly and obese individuals have ghrelin resistance, which is a key factor in aging. However, the efficacy of ghrelin for promoting longevity remains controversial. Further clinical studies are needed to clarify the mechanism of longevity.

3.2. Sarcopenia and Frailty

Ghrelin and ghrelin receptor agonists also improve skeletal muscle atrophy. Ghrelin shows anti-catabolic and anti-inflammatory effects, and leads to inhibition of catabolism of muscle proteins [89]. Age-related changes in muscle influence longevity and a healthy life expectancy. Ghrelin is effective in preventing sarcopenia and muscle atrophy in cancer cachexia [90]. Thus, ghrelin has been proposed as a treatment for sarcopenia. Ghrelin also prevents tumor implantation and cisplatin-induced muscle atrophy in vivo and in vitro, significantly increasing muscle mass and grip strength and improving survival. Ghrelin prevents muscle atrophy by down-regulating inflammation and p38/C/EBP-β/myostatin, and activating Akt, myogenin, and myoD [91].
Recently, an effect of des-acyl ghrelin on muscle has been reported. Des-acyl ghrelin induces skeletal muscle regeneration after ischemia via superoxide dismutase-2-induced miR-221/222 expression [92]. Des-acyl ghrelin restores the impaired insulin and autophagic signaling in the skeletal muscle of diabetic mice [93]. These studies indicate a preventive and repair effect of des-acyl ghrelin on skeletal muscle damage [93].
Aging is commonly associated with low-grade adipose inflammation and insulin resistance. Frailty is associated with an altered glucose-insulin axis. Ghrelin signaling plays an important role in macrophage polarization and adipose tissue inflammation during aging. Expression of GHS-R increases in adipose tissues during aging, and old Ghsr (−/−) mice exhibit a lean and insulin-sensitive phenotype [94]. It indicated to consider the use of ghrelin signaling antagonist to improve the body’s metabolism. However, recently study showed that ghrelin deficiency does not affect longevity in mice [95].
Elderly individuals with sarcopenia show significantly lower ghrelin levels than those without sarcopenia, but these differences disappeared when individuals were stratified by gender. The ghrelin levels of elderly subjects without sarcopenia are not decreased compared with young adults [96]. In addition, administration of an oral ghrelin mimetic to healthy older adults increases the total body weight and lean body mass, although no significant difference in muscle strength or quality of life was found [97]. In another study, administration of an oral ghrelin agonist increased tandem walking and stair climbing, as well as lean body mass [98]. Frail women have higher fasting levels of free fatty acid (FFA), resistin, GH, and interleukin-6 and lower fasting levels of ghrelin, adiponectin, glucagon-like peptide 1 (GLP-1), and IGF-1 compared with non-frail women, although the differences were not statistically significant [99].
The mutual interplay among energy homeostasis, acyl ghrelin and des-acyl ghrelin, and bone metabolism is also an important concept. Regulatory networks may exist between the orexigenic ghrelin pathway and bone metabolism, which is age dependent. Increases in food intake and direct effects on muscle proteolysis and protein synthesis are likely to mediate these effects, but the pathways leading to these events are not well understood. Acyl ghrelin inhibits osteoclast formation and induces osteoprotegerin gene expression [100]. Ghrelin and leptin antagonize each other and metabolically balance each other. Leptin suppresses osteoclastogenic activity via ghrelin receptors in a leptin-deficient animal model [101]. Additionally, osteoporosis in humans using growth hormone secretagogue receptor (GHSR) agonists has had minor success in post-menopausal women [102]. These studies suggest that the metabolic pathway, ghrelin, and leptin play an important role in frailty syndrome and bone metabolism.

3.3. Ghrelin and Memory

Increasing evidence suggests an association between ghrelin and Alzheimer’s disease pathology. Ghrelin therapy may be a potential strategy for preventing or treating neurodegenerative diseases. Previous studies have shown that ghrelin also affects mood, anxiety, cognition, and memory retention in addition to its role in metabolism and energy intake [103]. The hippocampus, amygdala, and dorsal raphe nucleus play a role in cognition [104,105], and the central serotonin system plays an important role in anxiety and memory. Memory retention is induced by ghrelin, whereas GHS-R1 depletion decreases serotonin activity [106,107,108]. In addition, decreased memory is improved by acute ghrelin administration [109,110]. Acute central administration of ghrelin to mice increases serotonergic turnover in the amygdala by affecting mRNA expression of a number of serotonin receptors, both in the amygdala and in the dorsal raphe [111]. Moreover, ghrelin mediated circadian rhythms via food intake in a recent study [112]. Ghrelin drives higher-order feeding processes related to food reward, food seeking, and learned and motivational aspects of feeding via CNS signaling through GHS-R1a [113]. A recent study suggested that ghrelin accelerates neurogenesis and activity development in cultured cortical networks [114]. Ghrelin increases survival and reduces cell death of hippocampal neurons and shows neuroprotective effects [115].
Ghrelin accelerates hippocampal synaptic plasticity and increases spatial memory via activation of PI3K [116]. Ghrelin administration affects long-term spine density of neurons in the hippocampus [117]. Acyl ghrelin expression in the amygdala is related to spatial learning through GHS-R1 [118]. GHS-R1a knockout mice exhibit improvements in spatial memory and deficits in contextual memory [119]. GHS-R1a is required for contextual memory, and GHS-R1a affects acquisition of spatial memory in the open field test and Morris water maze [119].
The neuroprotective mechanism of ghrelin in aging is considered to be an increase in Sirt1 activity in the brain and a decrease in microglial activity. An experiment to investigate an association between ghrelin and a ghrelin agonist and longevity was conducted using Klotho-deficient mice, senescence-accelerated mouse prone 8 (SAMP8 mice), and ICR mice. These three types of mice are models of accelerated senescence and aging. SAMP8 mice show an age-related increase in β-amyloid and a similar phenome as Alzheimer’s disease model mice. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 hastens death. Furthermore, the ghrelin agonists, rikkunshito and atractylodin, activate Sirt1, improve aging-related disease, and extend life span [58].

4. Effect of CR Mimetics and Ghrelin Agonists on Longevity

Many studies have been conducted on compounds with similar actions as CR including activation of Sirt1 and extension of life span (Table 1). Based on preliminary study results, the use of ghrelin mimetics may be more suitable for use in elderly individuals than GH itself. Resveratrol, a polyphenol found in grapes, is a representative CR mimetic. Rapamycin, 2-deoxy-d-glucose, and metformin also show similar effects as CR. The life span of mice is shortened by intake of a high-fat diet. However, when resveratrol, which activates Sirt1, was given, the life span of the high-fat diet-fed mice was not shortened [120]. The life span is not extended even if resveratrol is given to mice fed a normal diet. Mice given resveratrol show a gene expression pattern like that induced by CR, including maintenance of elasticity of blood vessels, and anti-aging effects such as a delay in the onset of cataracts and increased exercise ability [121]. Recently, the amino acid sequence of Sirt1 has been determined, and its active mechanism has been elucidated [122].
Rapamycin, which is an immunosuppressive drug, extends the life span of nematodes and yeast via TORC1 inhibition. Rapamycin also extends the life span of mice by inhibiting mTOR1, and this drug reduces phosphorylation of ribosomal protein S6 kinase 1 (S6K1), which is a main downstream effecter of mTOR1 [123]. In addition, rapamycin extends the life span of S6K1 knockout mice [124].
Rikkunshito, a traditional Japanese kampo, is composed of 43 ingredients. Rikkunshito is used in Japan to treat upper gastrointestinal symptoms in patients with functional dyspepsia (gastroesophageal reflux disease), dyspeptic symptoms in postgastrointestinal surgery patients, chemotherapy-induced dyspepsia in cancer patients, cancer cachexia syndrome, and anorexia due to aging. Oral administration of rikkunshito potentiates the orexigenic action of ghrelin through several different mechanisms [125]. In this review, we will highlight what is known about the orexigenic effect of rikkunshito with a special focus on the interaction with the ghrelin signaling system [126].
Dysregulation of ghrelin secretion and ghrelin resistance in the appetite control system occurs in aged mice. Rikkunshito ameliorates aging-associated anorexia via inhibition of phosphodiesterase 3 (PDE3) [84]. The effects of ghrelin, rikkunshito, PDE3, and PDE3 kinase inhibitors on appetite have been studied. Although ghrelin supplementation (33 μg/kg) failed to increase food intake in aged mice, oral administration of a PDE3 kinase inhibitor and a PDE3 inhibitor increases food intake in aged mice [84]. Rikkunshito also increases food intake in aged mice. Rikkunshito stimulates ghrelin secretion via serotonin2b/2c receptor antagonism, inhibits the ghrelin metabolic enzyme, improves ghrelin resistance [127], and reinforces ghrelin signaling by increasing GHS-R activity [128]. Rikkunshito promotes ghrelin secretion and reinforces ghrelin sensitivity in both the central and peripheral nervous systems.
Certain components of rikkunshito (nobiletin, isoliquiritigenin, and heptamethoxyflavone) have inhibitory effects on PDE3 [84]. Atractylodin is another main ingredient of rikkunshito, and it is detected as a major component in the plasma of volunteers given rikkunshito. Atractylodin extends the life span of Klotho-deficient mice. Atractylodin increases the calcium concentration in cells when ghrelin is added to cells that express GHS-R. Thus, rikkunshito and atractylodin show similar actions as CR via ghrelin-GHS-R signaling.
Rikkunshito enhances phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding protein through the ghrelin receptor and activates Sirt1. Interestingly, an active increase in Sirt1 was not seen if rikkunshito was given to ghrelin receptor knockout mice, suggesting that rikkunshito activates Sirt1 through ghrelin and the ghrelin receptor, leading to an extended life span. Rikkunshito increases Sirt1 activity through the ghrelin receptor and significantly extends the life span in three models of accelerated senescence and aging: Klotho-deficient mice, SAMP8 mice, and ICR mice [58].

5. Conclusions

We discussed the role of orexigenic peptides with a particular focus on ghrelin. Ghrelin-GHS-R signaling may play an important role in the mechanism of aging (Figure 1). CR mimetics and ghrelin mimetics may provide new hope for improving a healthy life expectancy in our aging society. However, controversy remains regarding the efficacy of ghrelin for enhancing longevity. Further clinical studies are needed to clarify the mechanism of longevity.


We appreciate the staff of Kagoshima University for their enthusiastic support.

Author Contributions

Drafting of the manuscript: Marie Amitani, Haruka Amitani, and Akio Inui. Obtained funding: Tetsuhiro Owaki. Administrative, technical, or material support: Nanami Sameshima, Kimiko Mizuma, Ippei Shimoshikiryo, Timothy Sean Kairupan, Natasya Trivena Rokot, Kai-Chun Cheng, Yasuhito Nerome, Tetsuhiro Owaki, Marie Amitani, and Akihiro Asakawa.

Conflicts of Interest

No author has relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.


AgRPAgouti-related protein
AMPKAdenosine monophosphate-activated protein kinase
cAMPCyclic adenosine monophosphate
CRCalorie restriction
FFAFree fatty acid
FOXOForkhead box O
GHSRGrowth hormone secretagogue receptor
GHSR-1aGrowth hormone secretagogue receptor-1a
GLP-1Glucagon-like peptide 1
HFDHigh fat diet
IGF-1Insulin-like growth factor 1
Irs2Insulin receptor substrate 2
NADNicotinamide adenine dinucleotide
NPYNeuropeptide Y
MC4RMelanocortin 4 receptor
mTOR1Mammalian TOR 1
PI3KPhosphatidylinositol 3-kinase
PGCPeroxisome proliferator-activated receptor-gamma coactivator
PparPeroxisome proliferator-activated receptor
SAMP8Senescence-accelerated mouse prone/8
S6K1Ribosomal protein S6 kinase 1
TORTarget of rapamycin
TORC1TOR complex 1
TORC2TOR complex 2


  1. Heemels, M.T. Ageing. Nature 2010, 464, 503. [Google Scholar] [CrossRef] [PubMed]
  2. Herskind, A.M.; McGue, M.; Holm, N.V.; Sorensen, T.I.; Harvald, B.; Vaupel, J.W. The heritability of human longevity: A population-based study of 2872 danish twin pairs born 1870–1900. Hum. Genet. 1996, 97, 319–323. [Google Scholar] [CrossRef] [PubMed]
  3. Tan, Q.; Zhao, J.H.; Zhang, D.; Kruse, T.A.; Christensen, K. Power for genetic association study of human longevity using the case-control design. Am. J. Epidemiol. 2008, 168, 890–896. [Google Scholar] [CrossRef] [PubMed]
  4. United Nations. World Population Ageing 2015; United Nations: New York, NY, USA, 2015. [Google Scholar]
  5. Cheng, K.C.; Li, Y.X.; Asakawa, A.; Inui, A. The role of ghrelin in energy homeostasis and its potential clinical relevance (review). Int. J. Mol. Med. 2010, 26, 771–778. [Google Scholar] [PubMed]
  6. Kaplan, R.C.; Strizich, G.; Aneke-Nash, C.; Dominguez-Islas, C.; Buzkova, P.; Strickler, H.; Rohan, T.; Pollak, M.; Kuller, L.; Kizer, J.R.; et al. Insulinlike growth factor binding protein-1 and ghrelin predict health outcomes among older adults: Cardiovascular health study cohort. J. Clin. Endocrinol. Metab. 2017, 102, 267–278. [Google Scholar] [PubMed]
  7. Friedman, D.B.; Johnson, T.E. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 1988, 118, 75–86. [Google Scholar] [PubMed]
  8. Morris, J.Z.; Tissenbaum, H.A.; Ruvkun, G. A phosphatidylinositol-3-oh kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 1996, 382, 536–539. [Google Scholar] [CrossRef] [PubMed]
  9. Tatar, M.; Bartke, A.; Antebi, A. The endocrine regulation of aging by insulin-like signals. Science 2003, 299, 1346–1351. [Google Scholar] [CrossRef] [PubMed]
  10. Vellai, T.; Takacs-Vellai, K.; Zhang, Y.; Kovacs, A.L.; Orosz, L.; Muller, F. Genetics: Influence of tor kinase on lifespan in C. Elegans. Nature 2003, 426, 620. [Google Scholar] [CrossRef] [PubMed]
  11. Bordone, L.; Guarente, L. Calorie restriction, sirt1 and metabolism: Understanding longevity. Nat. Rev. Mol. Cell Biol. 2005, 6, 298–305. [Google Scholar] [CrossRef] [PubMed]
  12. McCay, C.M.; Maynard, L.A. The effect of retarded growth upon the length of life span and upon the ultimate body size. J. Nutr. 1935, 10, 63–79. [Google Scholar]
  13. Mair, W.; Dillin, A. Aging and survival: The genetics of life span extension by dietary restriction. Annu. Rev. Biochem. 2008, 77, 727–754. [Google Scholar] [CrossRef] [PubMed]
  14. Colman, R.J.; Anderson, R.M.; Johnson, S.C.; Kastman, E.K.; Kosmatka, K.J.; Beasley, T.M.; Allison, D.B.; Cruzen, C.; Simmons, H.A.; Kemnitz, J.W.; et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009, 325, 201–204. [Google Scholar] [CrossRef] [PubMed]
  15. Mattison, J.A.; Roth, G.S.; Beasley, T.M.; Tilmont, E.M.; Handy, A.M.; Herbert, R.L.; Longo, D.L.; Allison, D.B.; Young, J.E.; Bryant, M.; et al. Impact of caloric restriction on health and survival in rhesus monkeys from the nia study. Nature 2012, 489, 318–321. [Google Scholar] [CrossRef] [PubMed]
  16. Ash, C.E.; Merry, B.J. The molecular basis by which dietary restricted feeding reduces mitochondrial reactive oxygen species generation. Mech. Ageing Dev. 2011, 132, 43–54. [Google Scholar] [CrossRef] [PubMed]
  17. Speakman, J.R.; Mitchell, S.E. Caloric restriction. Mol. Asp. Med. 2011, 32, 159–221. [Google Scholar] [CrossRef] [PubMed]
  18. Sonntag, W.E.; Xu, X.; Ingram, R.L.; D’Costa, A. Moderate caloric restriction alters the subcellular distribution of somatostatin mrna and increases growth hormone pulse amplitude in aged animals. Neuroendocrinology 1995, 61, 601–608. [Google Scholar] [CrossRef] [PubMed]
  19. Suzuki, M.; Wilcox, B.J.; Wilcox, C.D. Implications from and for food cultures for cardiovascular disease: Longevity. Asia Pac. J. Clin. Nutr. 2001, 10, 165–171. [Google Scholar] [CrossRef] [PubMed]
  20. Flegal, K.M.; Graubard, B.I.; Williamson, D.F.; Gail, M.H. Excess deaths associated with underweight, overweight, and obesity. JAMA 2005, 293, 1861–1867. [Google Scholar] [CrossRef] [PubMed]
  21. Zigman, J.M.; Bouret, S.G.; Andrews, Z.B. Obesity impairs the action of the neuroendocrine ghrelin system. Trends Endocrinol. Metab. 2016, 27, 54–63. [Google Scholar] [CrossRef] [PubMed]
  22. Martin, C.K.; Bhapkar, M.; Pittas, A.G.; Pieper, C.F.; Das, S.K.; Williamson, D.A.; Scott, T.; Redman, L.M.; Stein, R.; Gilhooly, C.H.; et al. Effect of calorie restriction on mood, quality of life, sleep, and sexual function in healthy nonobese adults: The calerie 2 randomized clinical trial. JAMA Intern. Med. 2016, 176, 743–752. [Google Scholar] [CrossRef] [PubMed]
  23. Leese, P.T.; Trang, J.M.; Blum, R.A.; de Groot, E. An open-label clinical trial of the effects of age and gender on the pharmacodynamics, pharmacokinetics and safety of the ghrelin receptor agonist anamorelin. Clin. Pharmacol. Drug Dev. 2015, 4, 112–120. [Google Scholar] [CrossRef] [PubMed]
  24. Kimura, K.D.; Tissenbaum, H.A.; Liu, Y.; Ruvkun, G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 1997, 277, 942–946. [Google Scholar] [CrossRef] [PubMed]
  25. Lakowski, B.; Hekimi, S. Determination of life-span in Caenorhabditis elegans by four clock genes. Science 1996, 272, 1010–1013. [Google Scholar] [CrossRef] [PubMed]
  26. Lin, S.J.; Defossez, P.A.; Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 2000, 289, 2126–2128. [Google Scholar] [CrossRef] [PubMed]
  27. Clancy, D.J.; Gems, D.; Harshman, L.G.; Oldham, S.; Stocker, H.; Hafen, E.; Leevers, S.J.; Partridge, L. Extension of life-span by loss of chico, a drosophila insulin receptor substrate protein. Science 2001, 292, 104–106. [Google Scholar] [CrossRef] [PubMed]
  28. D’Costa, A.P.; Lenham, J.E.; Ingram, R.L.; Sonntag, W.E. Moderate caloric restriction increases type 1 IGF receptors and protein synthesis in aging rats. Mech. Ageing Dev. 1993, 71, 59–71. [Google Scholar] [CrossRef]
  29. Rudman, D.; Feller, A.G.; Nagraj, H.S.; Gergans, G.A.; Lalitha, P.Y.; Goldberg, A.F.; Schlenker, R.A.; Cohn, L.; Rudman, I.W.; Mattson, D.E. Effects of human growth hormone in men over 60 years old. N. Engl. J. Med. 1990, 323, 1–6. [Google Scholar] [CrossRef] [PubMed]
  30. Zhou, M.; Yang, W.L.; Aziz, M.; Ma, G.; Wang, P. Therapeutic effect of human ghrelin and growth hormone: Attenuation of immunosuppression in septic aged rats. Biochim. Biophys. Acta 2017. [Google Scholar] [CrossRef] [PubMed]
  31. Giordano, R.; Bonelli, L.; Marinazzo, E.; Ghigo, E.; Arvat, E. Growth hormone treatment in human ageing: Benefits and risks. Hormones 2008, 7, 133–139. [Google Scholar] [PubMed]
  32. Liu, H.; Bravata, D.M.; Olkin, I.; Nayak, S.; Roberts, B.; Garber, A.M.; Hoffman, A.R. Systematic review: The safety and efficacy of growth hormone in the healthy elderly. Ann. Intern. Med. 2007, 146, 104–115. [Google Scholar] [CrossRef] [PubMed]
  33. Thorner, M.O. Statement by the growth hormone research society on the GH/IGF-I axis in extending health span. J. Gerontol. Biol. Sci. Med. Sci. 2009, 64, 1039–1044. [Google Scholar] [CrossRef] [PubMed]
  34. Kaeberlein, M.; McVey, M.; Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999, 13, 2570–2580. [Google Scholar] [CrossRef] [PubMed]
  35. Tissenbaum, H.A.; Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 2001, 410, 227–230. [Google Scholar] [CrossRef] [PubMed]
  36. Rogina, B.; Helfand, S.L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl. Acad. Sci. USA 2004, 101, 15998–16003. [Google Scholar] [CrossRef] [PubMed]
  37. Wang, Y.; Tissenbaum, H.A. Overlapping and distinct functions for a Caenorhabditis elegans SIR2 and DAF-16/FOXO. Mech. Ageing Dev. 2006, 127, 48–56. [Google Scholar] [CrossRef] [PubMed]
  38. Saunders, L.R.; Verdin, E. Sirtuins: Critical regulators at the crossroads between cancer and aging. Oncogene 2007, 26, 5489–5504. [Google Scholar] [CrossRef] [PubMed]
  39. Bordone, L.; Cohen, D.; Robinson, A.; Motta, M.C.; van Veen, E.; Czopik, A.; Steele, A.D.; Crowe, H.; Marmor, S.; Luo, J.; et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 2007, 6, 759–767. [Google Scholar] [CrossRef] [PubMed]
  40. Imai, S. SIRT1 and caloric restriction: An insight into possible trade-offs between robustness and frailty. Curr. Opin. Clin. Nutr. Metab. Care 2009, 12, 350–356. [Google Scholar] [CrossRef] [PubMed]
  41. Baur, J.A.; Ungvari, Z.; Minor, R.K.; Le Couteur, D.G.; de Cabo, R. Are sirtuins viable targets for improving healthspan and lifespan? Nat. Rev. Drug Discov. 2012, 11, 443–461. [Google Scholar] [CrossRef] [PubMed]
  42. Toorie, A.M.; Nillni, E.A. Minireview: Central sirt1 regulates energy balance via the melanocortin system and alternate pathways. Mol. Endocrinol. 2014, 28, 1423–1434. [Google Scholar] [CrossRef] [PubMed]
  43. Satoh, A.; Imai, S. Hypothalamic sirt1 in aging. Aging 2014, 6, 1–2. [Google Scholar] [CrossRef] [PubMed]
  44. Dietrich, M.O.; Antunes, C.; Geliang, G.; Liu, Z.W.; Borok, E.; Nie, Y.; Xu, A.W.; Souza, D.O.; Gao, Q.; Diano, S.; et al. Agrp neurons mediate sirt1’s action on the melanocortin system and energy balance: Roles for sirt1 in neuronal firing and synaptic plasticity. J. Neurosci. 2010, 30, 11815–11825. [Google Scholar] [CrossRef] [PubMed]
  45. Takeshita, K.; Fujimori, T.; Kurotaki, Y.; Honjo, H.; Tsujikawa, H.; Yasui, K.; Lee, J.K.; Kamiya, K.; Kitaichi, K.; Yamamoto, K.; et al. Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression. Circulation 2004, 109, 1776–1782. [Google Scholar] [CrossRef] [PubMed]
  46. Kawaguchi, H.; Manabe, N.; Miyaura, C.; Chikuda, H.; Nakamura, K.; Kuro-o, M. Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia. J. Clin. Investig. 1999, 104, 229–237. [Google Scholar] [CrossRef] [PubMed]
  47. Nagai, T.; Yamada, K.; Kim, H.C.; Kim, Y.S.; Noda, Y.; Imura, A.; Nabeshima, Y.; Nabeshima, T. Cognition impairment in the genetic model of aging klotho gene mutant mice: A role of oxidative stress. FASEB J. 2003, 17, 50–52. [Google Scholar] [CrossRef] [PubMed]
  48. Suga, T.; Kurabayashi, M.; Sando, Y.; Ohyama, Y.; Maeno, T.; Maeno, Y.; Aizawa, H.; Matsumura, Y.; Kuwaki, T.; Kuro, O.M.; et al. Disruption of the klotho gene causes pulmonary emphysema in mice. Defect in maintenance of pulmonary integrity during postnatal life. Am. J. Respir. Cell Mol. Biol. 2000, 22, 26–33. [Google Scholar] [CrossRef] [PubMed]
  49. Shimada, T.; Hasegawa, H.; Yamazaki, Y.; Muto, T.; Hino, R.; Takeuchi, Y.; Fujita, T.; Nakahara, K.; Fukumoto, S.; Yamashita, T. FGF-23 is a potent regulator of vitamin d metabolism and phosphate homeostasis. J. Bone Miner. Res. 2004, 19, 429–435. [Google Scholar] [CrossRef] [PubMed]
  50. Amitani, M.; Asakawa, A.; Amitani, H.; Kaimoto, K.; Sameshima, N.; Koyama, K.I.; Haruta, I.; Tsai, M.; Nakahara, T.; Ushikai, M.; et al. Plasma klotho levels decrease in both anorexia nervosa and obesity. Nutrition 2013, 29, 1106–1109. [Google Scholar] [CrossRef] [PubMed]
  51. Laplante, M.; Sabatini, D.M. Mtor signaling in growth control and disease. Cell 2012, 149, 274–293. [Google Scholar] [CrossRef] [PubMed]
  52. Hay, N.; Sonenberg, N. Upstream and downstream of mtor. Genes Dev. 2004, 18, 1926–1945. [Google Scholar] [CrossRef] [PubMed]
  53. Salminen, A.; Kaarniranta, K. Regulation of the aging process by autophagy. Trends Mol. Med. 2009, 15, 217–224. [Google Scholar] [CrossRef] [PubMed]
  54. Hands, S.L.; Proud, C.G.; Wyttenbach, A. Mtor’s role in ageing: Protein synthesis or autophagy? Aging 2009, 1, 586–597. [Google Scholar] [CrossRef] [PubMed]
  55. Jia, K.; Chen, D.; Riddle, D.L. The TOR pathway interacts with the insulin signaling pathway to regulate C. Elegans larval development, metabolism and life span. Development 2004, 131, 3897–3906. [Google Scholar] [CrossRef] [PubMed]
  56. Pan, K.Z.; Palter, J.E.; Rogers, A.N.; Olsen, A.; Chen, D.; Lithgow, G.J.; Kapahi, P. Inhibition of mrna translation extends lifespan in Caenorhabditis elegans. Aging Cell 2007, 6, 111–119. [Google Scholar] [CrossRef] [PubMed]
  57. Igarashi, M.; Guarente, L. Mtorc1 and sirt1 cooperate to foster expansion of gut adult stem cells during calorie restriction. Cell 2016, 166, 436–450. [Google Scholar] [CrossRef] [PubMed]
  58. Fujitsuka, N.; Asakawa, A.; Morinaga, A.; Amitani, M.S.; Amitani, H.; Katsuura, G.; Sawada, Y.; Sudo, Y.; Uezono, Y.; Mochiki, E.; et al. Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1. Mol. Psychiatry 2016, 21, 1613–1623. [Google Scholar] [CrossRef] [PubMed]
  59. Reimer, R.A.; Maurer, A.D.; Lau, D.C.; Auer, R.N. Long-term dietary restriction influences plasma ghrelin and goat mrna level in rats. Physiol. Behav. 2010, 99, 605–610. [Google Scholar] [CrossRef] [PubMed]
  60. Dunn, I.C.; Wilson, P.W.; Smulders, T.V.; Sandilands, V.; D’Eath, R.B.; Boswell, T. Hypothalamic agouti-related protein expression is affected by both acute and chronic experience of food restriction and re-feeding in chickens. J. Neuroendocrinol. 2013, 25, 920–928. [Google Scholar] [CrossRef] [PubMed]
  61. Ferreira-Marques, M.; Aveleira, C.A.; Carmo-Silva, S.; Botelho, M.; Pereira de Almeida, L.; Cavadas, C. Caloric restriction stimulates autophagy in rat cortical neurons through neuropeptide Y and ghrelin receptors activation. Aging 2016, 8, 1470–1484. [Google Scholar] [CrossRef] [PubMed]
  62. Aveleira, C.A.; Botelho, M.; Carmo-Silva, S.; Pascoal, J.F.; Ferreira-Marques, M.; Nobrega, C.; Cortes, L.; Valero, J.; Sousa-Ferreira, L.; Alvaro, A.R.; et al. Neuropeptide y stimulates autophagy in hypothalamic neurons. Proc. Natl. Acad. Sci. USA 2015, 112, E1642–E1651. [Google Scholar] [CrossRef] [PubMed]
  63. Aveleira, C.A.; Botelho, M.; Cavadas, C. NPY/neuropeptide Y enhances autophagy in the hypothalamus: A mechanism to delay aging? Autophagy 2015, 11, 1431–1433. [Google Scholar] [CrossRef] [PubMed]
  64. Veyrat-Durebex, C.; Quirion, R.; Ferland, G.; Dumont, Y.; Gaudreau, P. Aging and long-term caloric restriction regulate neuropeptide Y receptor subtype densities in the rat brain. Neuropeptides 2013, 47, 163–169. [Google Scholar] [CrossRef] [PubMed]
  65. Chiba, T.; Tamashiro, Y.; Park, D.; Kusudo, T.; Fujie, R.; Komatsu, T.; Kim, S.E.; Park, S.; Hayashi, H.; Mori, R.; et al. A key role for neuropeptide y in lifespan extension and cancer suppression via dietary restriction. Sci. Rep. 2014, 4, 4517. [Google Scholar] [CrossRef] [PubMed]
  66. Inui, A. Ghrelin: An orexigenic and somatotrophic signal from the stomach. Nat. Rev. Neurosci. 2001, 2, 551–560. [Google Scholar] [CrossRef] [PubMed]
  67. Kojima, M.; Hosoda, H.; Date, Y.; Nakazato, M.; Matsuo, H.; Kangawa, K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999, 402, 656–660. [Google Scholar] [CrossRef] [PubMed]
  68. Fujino, K.; Inui, A.; Asakawa, A.; Kihara, N.; Fujimura, M.; Fujimiya, M. Ghrelin induces fasted motor activity of the gastrointestinal tract in conscious fed rats. J. Physiol. 2003, 550, 227–240. [Google Scholar] [CrossRef] [PubMed]
  69. Kishimoto, I.; Tokudome, T.; Hosoda, H.; Miyazato, M.; Kangawa, K. Ghrelin and cardiovascular diseases. J. Cardiol. 2012, 59, 8–13. [Google Scholar] [CrossRef] [PubMed]
  70. Dezaki, K.; Hosoda, H.; Kakei, M.; Hashiguchi, S.; Watanabe, M.; Kangawa, K.; Yada, T. Endogenous ghrelin in pancreatic islets restricts insulin release by attenuating Ca2+ signaling in β-cells: Implication in the glycemic control in rodents. Diabetes 2004, 53, 3142–3151. [Google Scholar] [CrossRef] [PubMed]
  71. Wang, Y.; Nishi, M.; Doi, A.; Shono, T.; Furukawa, Y.; Shimada, T.; Furuta, H.; Sasaki, H.; Nanjo, K. Ghrelin inhibits insulin secretion through the AMPK-UCP2 pathway in β cells. FEBS Lett. 2010, 584, 1503–1508. [Google Scholar] [CrossRef] [PubMed]
  72. Granado, M.; Priego, T.; Martin, A.I.; Villanua, M.A.; Lopez-Calderon, A. Anti-inflammatory effect of the ghrelin agonist growth hormone-releasing peptide-2 (GHRP-2) in arthritic rats. Am. J. Physiol. Endocrinol. Metab. 2005, 288, E486–E492. [Google Scholar] [CrossRef] [PubMed]
  73. Yin, Y.; Zhang, W. The role of ghrelin in senescence: A mini-review. Gerontology 2016, 62, 155–162. [Google Scholar] [CrossRef] [PubMed]
  74. Laviano, A.; Molfino, A.; Rianda, S.; Rossi Fanelli, F. The growth hormone secretagogue receptor (Ghs-R). Curr. Pharm. Des. 2012, 18, 4749–4754. [Google Scholar] [CrossRef] [PubMed]
  75. Bayliss, J.A.; Andrews, Z.B. Ghrelin is the metabolic link connecting calorie restriction to neuroprotection. Neural Regen. Res. 2016, 11, 1228–1229. [Google Scholar] [PubMed]
  76. Rogers, N.H.; Walsh, H.; Alvarez-Garcia, O.; Park, S.; Gaylinn, B.; Thorner, M.O.; Smith, R.G. Metabolic benefit of chronic caloric restriction and activation of hypothalamic AGRP/NPY neurons in male mice is independent of ghrelin. Endocrinology 2016, 157, 1430–1442. [Google Scholar] [CrossRef] [PubMed]
  77. Girardet, C.; Mavrikaki, M.; Southern, M.R.; Smith, R.G.; Butler, A.A. Assessing interactions between ghsr and Mc3r reveals a role for AgRP in the expression of food anticipatory activity in male mice. Endocrinology 2014, 155, 4843–4855. [Google Scholar] [CrossRef] [PubMed]
  78. Lin, L.; Lee, J.H.; Bongmba, O.Y.; Ma, X.; Zhu, X.; Sheikh-Hamad, D.; Sun, Y. The suppression of ghrelin signaling mitigates age-associated thermogenic impairment. Aging 2014, 6, 1019–1032. [Google Scholar] [CrossRef] [PubMed]
  79. Wu, C.S.; Bongmba, O.Y.N.; Yue, J.; Lee, J.H.; Lin, L.; Saito, K.; Pradhan, G.; Li, D.P.; Pan, H.L.; Xu, A.; et al. Suppression of GHS-R in AgRP neurons mitigates diet-induced obesity by activating thermogenesis. Int. J. Mol. Sci. 2017, 18, 832. [Google Scholar] [CrossRef] [PubMed]
  80. Wang, W.M.; Li, S.M.; Du, F.M.; Zhu, Z.C.; Zhang, J.C.; Li, Y.X. Ghrelin and obestatin levels in hypertensive obese patients. J. Int. Med. Res. 2014, 42, 1202–1208. [Google Scholar] [CrossRef] [PubMed]
  81. Dieguez, C.; Vazquez, M.J.; Romero, A.; Lopez, M.; Nogueiras, R. Hypothalamic control of lipid metabolism: Focus on leptin, ghrelin and melanocortins. Neuroendocrinology 2011, 94, 1–11. [Google Scholar] [CrossRef] [PubMed]
  82. Boghossian, S.; Ueno, N.; Dube, M.G.; Kalra, P.; Kalra, S. Leptin gene transfer in the hypothalamus enhances longevity in adult monogenic mutant mice in the absence of circulating leptin. Neurobiol. Aging 2007, 28, 1594–1604. [Google Scholar] [CrossRef] [PubMed]
  83. Briggs, D.I.; Lockie, S.H.; Benzler, J.; Wu, Q.; Stark, R.; Reichenbach, A.; Hoy, A.J.; Lemus, M.B.; Coleman, H.A.; Parkington, H.C.; et al. Evidence that diet-induced hyperleptinemia, but not hypothalamic gliosis, causes ghrelin resistance in NPY/AgRP neurons of male mice. Endocrinology 2014, 155, 2411–2422. [Google Scholar] [CrossRef] [PubMed]
  84. Takeda, H.; Muto, S.; Hattori, T.; Sadakane, C.; Tsuchiya, K.; Katsurada, T.; Ohkawara, T.; Oridate, N.; Asaka, M. Rikkunshito ameliorates the aging-associated decrease in ghrelin receptor reactivity via phosphodiesterase III inhibition. Endocrinology 2010, 151, 244–252. [Google Scholar] [CrossRef] [PubMed]
  85. Stenholm, S.; Metter, E.J.; Roth, G.S.; Ingram, D.K.; Mattison, J.A.; Taub, D.D.; Ferrucci, L. Relationship between plasma ghrelin, insulin, leptin, interleukin 6, adiponectin, testosterone and longevity in the baltimore longitudinal study of aging. Aging Clin. Exp. Res. 2011, 23, 153–158. [Google Scholar] [CrossRef] [PubMed]
  86. De Vriese, C.; Gregoire, F.; Lema-Kisoka, R.; Waelbroeck, M.; Robberecht, P.; Delporte, C. Ghrelin degradation by serum and tissue homogenates: Identification of the cleavage sites. Endocrinology 2004, 145, 4997–5005. [Google Scholar] [CrossRef] [PubMed]
  87. Goliasch, G.; Haschemi, A.; Marculescu, R.; Endler, G.; Maurer, G.; Wagner, O.; Huber, K.; Mannhalter, C.; Niessner, A. Butyrylcholinesterase activity predicts long-term survival in patients with coronary artery disease. Clin. Chem. 2012, 58, 1055–1058. [Google Scholar] [CrossRef] [PubMed]
  88. Brimijoin, S.; Chen, V.P.; Pang, Y.P.; Geng, L.; Gao, Y. Physiological roles for butyrylcholinesterase: A BChE-ghrelin axis. Chem.-Biol. Interact. 2016, 259, 271–275. [Google Scholar] [CrossRef] [PubMed]
  89. Amitani, M.; Asakawa, A.; Amitani, H.; Inui, A. Control of food intake and muscle wasting in cachexia. Int. J. Biochem. Cell Biol. 2013, 45, 2179–2185. [Google Scholar] [CrossRef] [PubMed]
  90. Wang, W.; Andersson, M.; Iresjo, B.M.; Lonnroth, C.; Lundholm, K. Effects of ghrelin on anorexia in tumor-bearing mice with eicosanoid-related cachexia. Int. J. Oncol. 2006, 28, 1393–1400. [Google Scholar] [CrossRef] [PubMed]
  91. Chen, J.A.; Splenser, A.; Guillory, B.; Luo, J.; Mendiratta, M.; Belinova, B.; Halder, T.; Zhang, G.; Li, Y.P.; Garcia, J.M. Ghrelin prevents tumour- and cisplatin-induced muscle wasting: Characterization of multiple mechanisms involved. J. Cachexia Sarcopenia Muscle 2015, 6, 132–143. [Google Scholar] [CrossRef] [PubMed]
  92. Togliatto, G.; Trombetta, A.; Dentelli, P.; Cotogni, P.; Rosso, A.; Tschop, M.H.; Granata, R.; Ghigo, E.; Brizzi, M.F. Unacylated ghrelin promotes skeletal muscle regeneration following hindlimb ischemia via SOD-2-mediated miR-221/222 expression. J. Am. Heart Assoc. 2013, 2, e000376. [Google Scholar] [CrossRef] [PubMed]
  93. Tam, B.T.; Pei, X.M.; Yung, B.Y.; Yip, S.P.; Chan, L.W.; Wong, C.S.; Siu, P.M. Unacylated ghrelin restores insulin and autophagic signaling in skeletal muscle of diabetic mice. Pflug. Arch. 2015, 467, 2555–2569. [Google Scholar] [CrossRef] [PubMed]
  94. Lin, L.; Lee, J.H.; Buras, E.D.; Yu, K.; Wang, R.; Smith, C.W.; Wu, H.; Sheikh-Hamad, D.; Sun, Y. Ghrelin receptor regulates adipose tissue inflammation in aging. Aging 2016, 8, 178–191. [Google Scholar] [CrossRef] [PubMed]
  95. Guillory, B.; Chen, J.A.; Patel, S.; Luo, J.; Splenser, A.; Mody, A.; Ding, M.; Baghaie, S.; Anderson, B.; Iankova, B.; et al. Deletion of ghrelin prevents aging-associated obesity and muscle dysfunction without affecting longevity. Aging Cell 2017. [Google Scholar] [CrossRef] [PubMed]
  96. Serra-Prat, M.; Papiol, M.; Monteis, R.; Palomera, E.; Cabre, M. Relationship between plasma ghrelin levels and sarcopenia in elderly subjects: A cross-sectional study. J. Nutr. Health Aging 2015, 19, 669–672. [Google Scholar] [CrossRef] [PubMed]
  97. Nass, R.; Pezzoli, S.S.; Oliveri, M.C.; Patrie, J.T.; Harrell, F.E., Jr.; Clasey, J.L.; Heymsfield, S.B.; Bach, M.A.; Vance, M.L.; Thorner, M.O. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: A randomized trial. Ann. Intern. Med. 2008, 149, 601–611. [Google Scholar] [CrossRef] [PubMed]
  98. White, H.K.; Petrie, C.D.; Landschulz, W.; MacLean, D.; Taylor, A.; Lyles, K.; Wei, J.Y.; Hoffman, A.R.; Salvatori, R.; Ettinger, M.P.; et al. Effects of an oral growth hormone secretagogue in older adults. J. Clin. Endocrinol. Metab. 2009, 94, 1198–1206. [Google Scholar] [CrossRef] [PubMed]
  99. Kalyani, R.R.; Varadhan, R.; Weiss, C.O.; Fried, L.P.; Cappola, A.R. Frailty status and altered dynamics of circulating energy metabolism hormones after oral glucose in older women. J. Nutr. Health Aging 2012, 16, 679–686. [Google Scholar] [CrossRef] [PubMed]
  100. Delhanty, P.J.; van der Velde, M.; van der Eerden, B.C.; Sun, Y.; Geminn, J.M.; van der Lely, A.J.; Smith, R.G.; van Leeuwen, J.P. Genetic manipulation of the ghrelin signaling system in male mice reveals bone compartment specificity of acylated and unacylated ghrelin in the regulation of bone remodeling. Endocrinology 2014, 155, 4287–4295. [Google Scholar] [CrossRef] [PubMed]
  101. Van der Velde, M.; van der Eerden, B.C.; Sun, Y.; Almering, J.M.; van der Lely, A.J.; Delhanty, P.J.; Smith, R.G.; van Leeuwen, J.P. An age-dependent interaction with leptin unmasks ghrelin’s bone-protective effects. Endocrinology 2012, 153, 3593–3602. [Google Scholar] [CrossRef] [PubMed]
  102. Smith, R.G.; Sun, Y.; Jiang, H.; Albarran-Zeckler, R.; Timchenko, N. Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging. Ann. N. Y. Acad. Sci. 2007, 1119, 147–164. [Google Scholar] [CrossRef] [PubMed]
  103. Carlini, V.P.; Monzon, M.E.; Varas, M.M.; Cragnolini, A.B.; Schioth, H.B.; Scimonelli, T.N.; de Barioglio, S.R. Ghrelin increases anxiety-like behavior and memory retention in rats. Biochem. Biophys. Res. Commun. 2002, 299, 739–743. [Google Scholar] [CrossRef]
  104. Fanselow, M.S.; Dong, H.W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 2010, 65, 7–19. [Google Scholar] [CrossRef] [PubMed]
  105. Carlini, V.P.; Varas, M.M.; Cragnolini, A.B.; Schioth, H.B.; Scimonelli, T.N.; de Barioglio, S.R. Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem. Biophys. Res. Commun. 2004, 313, 635–641. [Google Scholar] [CrossRef] [PubMed]
  106. Carlini, V.P.; Gaydou, R.C.; Schioth, H.B.; de Barioglio, S.R. Selective serotonin reuptake inhibitor (fluoxetine) decreases the effects of ghrelin on memory retention and food intake. Regul. Pept. 2007, 140, 65–73. [Google Scholar] [CrossRef] [PubMed]
  107. Patterson, Z.R.; Ducharme, R.; Anisman, H.; Abizaid, A. Altered metabolic and neurochemical responses to chronic unpredictable stressors in ghrelin receptor-deficient mice. Eur. J. Neurosci. 2010, 32, 632–639. [Google Scholar] [CrossRef] [PubMed]
  108. Diano, S.; Farr, S.A.; Benoit, S.C.; McNay, E.C.; da Silva, I.; Horvath, B.; Gaskin, F.S.; Nonaka, N.; Jaeger, L.B.; Banks, W.A.; et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat. Neurosci. 2006, 9, 381–388. [Google Scholar] [CrossRef] [PubMed]
  109. Carvajal, P.; Carlini, V.P.; Schioth, H.B.; de Barioglio, S.R.; Salvatierra, N.A. Central ghrelin increases anxiety in the open field test and impairs retention memory in a passive avoidance task in neonatal chicks. Neurobiol. Learn. Mem. 2009, 91, 402–407. [Google Scholar] [CrossRef] [PubMed]
  110. Carlini, V.P.; Martini, A.C.; Schioth, H.B.; Ruiz, R.D.; Fiol de Cuneo, M.; de Barioglio, S.R. Decreased memory for novel object recognition in chronically food-restricted mice is reversed by acute ghrelin administration. Neuroscience 2008, 153, 929–934. [Google Scholar] [CrossRef] [PubMed]
  111. Hansson, C.; Alvarez-Crespo, M.; Taube, M.; Skibicka, K.P.; Schmidt, L.; Karlsson-Lindahl, L.; Egecioglu, E.; Nissbrandt, H.; Dickson, S.L. Influence of ghrelin on the central serotonergic signaling system in mice. Neuropharmacology 2014, 79, 498–505. [Google Scholar] [CrossRef] [PubMed]
  112. Kent, B.A. Synchronizing an aging brain: Can entraining circadian clocks by food slow alzheimer’s disease? Front. Aging Neurosci. 2014, 6, 234. [Google Scholar] [CrossRef] [PubMed]
  113. Kanoski, S.E.; Fortin, S.M.; Ricks, K.M.; Grill, H.J. Ghrelin signaling in the ventral hippocampus stimulates learned and motivational aspects of feeding via PI3K-Akt signaling. Biol. Psychiatry 2013, 73, 915–923. [Google Scholar] [CrossRef] [PubMed]
  114. Stoyanova, I.I.; le Feber, J. Ghrelin accelerates synapse formation and activity development in cultured cortical networks. BMC Neurosci. 2014, 15, 49. [Google Scholar] [CrossRef] [PubMed]
  115. Liu, Y.; Wang, P.S.; Xie, D.; Liu, K.; Chen, L. Ghrelin reduces injury of hippocampal neurons in a rat model of cerebral ischemia/reperfusion. Chin. J. Physiol. 2006, 49, 244–250. [Google Scholar] [PubMed]
  116. Chen, L.; Xing, T.; Wang, M.; Miao, Y.; Tang, M.; Chen, J.; Li, G.; Ruan, D.Y. Local infusion of ghrelin enhanced hippocampal synaptic plasticity and spatial memory through activation of phosphoinositide 3-kinase in the dentate gyrus of adult rats. Eur. J. Neurosci. 2011, 33, 266–275. [Google Scholar] [CrossRef] [PubMed]
  117. Berrout, L.; Isokawa, M. Ghrelin promotes reorganization of dendritic spines in cultured rat hippocampal slices. Neurosci. Lett. 2012, 516, 280–284. [Google Scholar] [CrossRef] [PubMed]
  118. Toth, K.; Laszlo, K.; Lenard, L. Role of intraamygdaloid acylated-ghrelin in spatial learning. Brain Res. Bull. 2010, 81, 33–37. [Google Scholar] [CrossRef] [PubMed]
  119. Albarran-Zeckler, R.G.; Brantley, A.F.; Smith, R.G. Growth hormone secretagogue receptor (GHS-R1A) knockout mice exhibit improved spatial memory and deficits in contextual memory. Behav. Brain Res. 2012, 232, 13–19. [Google Scholar] [CrossRef] [PubMed]
  120. Baur, J.A.; Pearson, K.J.; Price, N.L.; Jamieson, H.A.; Lerin, C.; Kalra, A.; Prabhu, V.V.; Allard, J.S.; Lopez-Lluch, G.; Lewis, K.; et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006, 444, 337–342. [Google Scholar] [CrossRef] [PubMed]
  121. Pearson, K.J.; Baur, J.A.; Lewis, K.N.; Peshkin, L.; Price, N.L.; Labinskyy, N.; Swindell, W.R.; Kamara, D.; Minor, R.K.; Perez, E.; et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 2008, 8, 157–168. [Google Scholar] [CrossRef] [PubMed]
  122. Imai, S. A possibility of nutriceuticals as an anti-aging intervention: Activation of sirtuins by promoting mammalian NAD biosynthesis. Pharmacol. Res. 2010, 62, 42–47. [Google Scholar] [CrossRef] [PubMed]
  123. Harrison, D.E.; Strong, R.; Sharp, Z.D.; Nelson, J.F.; Astle, C.M.; Flurkey, K.; Nadon, N.L.; Wilkinson, J.E.; Frenkel, K.; Carter, C.S.; et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009, 460, 392–395. [Google Scholar] [CrossRef] [PubMed]
  124. Selman, C.; Tullet, J.M.; Wieser, D.; Irvine, E.; Lingard, S.J.; Choudhury, A.I.; Claret, M.; Al-Qassab, H.; Carmignac, D.; Ramadani, F.; et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 2009, 326, 140–144. [Google Scholar] [CrossRef] [PubMed]
  125. Takeda, H.; Muto, S.; Nakagawa, K.; Ohnishi, S.; Sadakane, C.; Saegusa, Y.; Nahata, M.; Hattori, T.; Asaka, M. Rikkunshito as a ghrelin enhancer. Methods Enzymol. 2012, 514, 333–351. [Google Scholar] [PubMed]
  126. Takeda, H.; Muto, S.; Nakagawa, K.; Ohnishi, S.; Asaka, M. Rikkunshito and ghrelin secretion. Curr. Pharm. Des. 2012, 18, 4827–4838. [Google Scholar] [CrossRef] [PubMed]
  127. Terawaki, K.; Kashiwase, Y.; Sawada, Y.; Hashimoto, H.; Yoshimura, M.; Ohbuchi, K.; Sudo, Y.; Suzuki, M.; Miyano, K.; Shiraishi, S.; et al. Development of ghrelin resistance in a cancer cachexia rat model using human gastric cancer-derived 85As2 cells and the palliative effects of the kampo medicine rikkunshito on the model. PLoS ONE 2017, 12, e0173113. [Google Scholar] [CrossRef] [PubMed]
  128. Fujitsuka, N.; Asakawa, A.; Hayashi, M.; Sameshima, M.; Amitani, H.; Kojima, S.; Fujimiya, M.; Inui, A. Selective serotonin reuptake inhibitors modify physiological gastrointestinal motor activities via 5-HT2c receptor and acyl ghrelin. Biol. Psychiatry 2009, 65, 748–759. [Google Scholar] [CrossRef] [PubMed]
Figure 1. CR increases the expression of hypothalamic AgRP and NPY and reduces the expression of POMC. NPY promotes autophagy in the hypothalamus. Ghrelin also affects the cardiovascular system, muscle, bone, and memory retention, as well as providing a neuroprotective effect, all of which result in an extended life span and anti-aging effects. CR: caloric restriction; AgRP: agouti-related protein; POMC: proopiomelanocortin; NPY: neuropeptide Y.
Figure 1. CR increases the expression of hypothalamic AgRP and NPY and reduces the expression of POMC. NPY promotes autophagy in the hypothalamus. Ghrelin also affects the cardiovascular system, muscle, bone, and memory retention, as well as providing a neuroprotective effect, all of which result in an extended life span and anti-aging effects. CR: caloric restriction; AgRP: agouti-related protein; POMC: proopiomelanocortin; NPY: neuropeptide Y.
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Table 1. Ghrelin and longevity.
Table 1. Ghrelin and longevity.
FormulaModelReported OutcomeStudyReferences
GhrelinRat cortical neuronsStimulation of network formation and activation in cortical neuronal networksIn vitroVeyrat-Durebex C et al., 2013 [64]
Ghrelin and Ghrelin antagonistRat cortical neuronsCaloric restriction mimetic cell culture medium stimulated autophagy in rat cortical neurons and ghrelin receptor antagonists blocked this effect. On the other hand, exogenous ghrelin stimulated autophagy in rat cortical neurons.In vitroFerreira-Marques M et al., 2016 [61]
GhrelinNormal ratsIncrease in memory retentionIn vivoCarlini VP et al., 2002 [103]
GhrelinSAMP8 (Alzheimer’s disease model)Improvement of retention on the T-maze foot shock avoidance taskIn vivoDiano et al., 2006 [108]
GhrelinCerebral ischemia/reperfusion rat modelIncrease in survival and reduce cell death of hippocampal neurons following ischemia/reperfusion injuryIn vivoLiu Y et al., 2006 [115]
GhrelinNormal ratsSSRI decreased the effects of ghrelin on memory retentionIn vivoCarlini VP et al., 2007 [106]
GhrelinNormal miceIncrease in the impaired memory of mice with 50% food restrictionIn vivoCarlini VP et al., 2008 [110]
Ghrelin mimetic6- and 75-week-old C57BL/6J miceAmelioration of aging-associated anorexia in mice via inhibition of PDE3In vivoTakeda et al., 2010 [84]
Ghrelin agonist and mimeticKlotho-deficient, SAMP8 and ICR miceDecrease in microglial activation in the brain and prolongation of survival in klotho-deficient, SAMP8 and aged ICR miceIn vitro and vivoFujitsuka et al., 2016 [58]
Ghrelin and GHSeptic aged ratsPrevention of the loss of splenic T cells and improvement of sepsis-induced immunosuppressionIn vivoZhou et al., 2017 [30]
GhrelinObese womenObesity-linked reductions in ghrelin were reversed by weight loss achieved through caloric restrictionClinicalBayliss JA et al., 2016 [75]
Ghrelin mimeticHealthy older adults, randomized, double-blind, placebo-controlled studyIncrease in total body weight and lean body mass. However, no significant difference in muscle strength, function and quality of lifeClinicalNass R et al., 2008 [97]
Ghrelin agonistHealthy older adults, randomized, double-blind, placebo-controlled studyIncrease in lean mass, tandem walk and stair climbClinicalWhite HK et al., 2009 [98]
BChEPatients with coronary artery diseasePresentation of CAD affected the effect of BChE on mortalityClinicalGoliasch G et al., 2012 [87]
GhrelinHealthy older adults, cohort studyGhrelin measured during an OGTT predicted major health events and death in older adultsClinicalKaplan RC et al., 2017 [6]
SAMP8, senescence-accelerated mouse prone/8; SSRI, selective Serotonin Reuptake Inhibitors; PDE3, phosphodiesterase 3; ICR, intermittent calorie restriction; GH, Growth hormone; CAD: coronary artery disease; BChE, butyrylcholinesterase; OGTT: oral glucose tolerance test.

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Amitani, M.; Amitani, H.; Cheng, K.-C.; Kairupan, T.S.; Sameshima, N.; Shimoshikiryo, I.; Mizuma, K.; Rokot, N.T.; Nerome, Y.; Owaki, T.; et al. The Role of Ghrelin and Ghrelin Signaling in Aging. Int. J. Mol. Sci. 2017, 18, 1511.

AMA Style

Amitani M, Amitani H, Cheng K-C, Kairupan TS, Sameshima N, Shimoshikiryo I, Mizuma K, Rokot NT, Nerome Y, Owaki T, et al. The Role of Ghrelin and Ghrelin Signaling in Aging. International Journal of Molecular Sciences. 2017; 18(7):1511.

Chicago/Turabian Style

Amitani, Marie, Haruka Amitani, Kai-Chun Cheng, Timothy Sean Kairupan, Nanami Sameshima, Ippei Shimoshikiryo, Kimiko Mizuma, Natasya Trivena Rokot, Yasuhito Nerome, Tetsuhiro Owaki, and et al. 2017. "The Role of Ghrelin and Ghrelin Signaling in Aging" International Journal of Molecular Sciences 18, no. 7: 1511.

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