Ghrelin hunger, obesity and aging

Have you heard about Ghrelin?  No, I am not talking about a new grill cleaner or a men’s girl-attracting perfume or a new shortstop for the Yankees.  Ghrelin is a hormone deeply involved in a very important current health condition, obesity, and it also plays critical roles in other key processes including neural functioning and learning. This blog is an introduction to Ghrelin and some of the important current research related to it.

About Ghrelin

The 2006 paper Gastrointestinal hormones (not including pancreatic hormones): Drug Insight: the functions of ghrelin and its potential as a multitherapeutic hormone summarizes some key aspects of the ghrelin story.  “The endogenous ligand for the growth-hormone (GH) secretagogue receptor was purified from stomach and named ghrelin. It has potent GH-releasing activity and stimulates appetite by acting on the hypothalamic arcuate nucleus, a region known to control food intake. Ghrelin thus plays important roles in maintaining GH release and energy homeostasis in vertebrates. Ghrelin, moreover, stimulates gastric motility and acid secretion, shows positive cardiovascular effects, and has direct actions on bone formation. The diverse functions of ghrelin raise the possibility of its clinical application for GH deficiency, eating disorders, gastrointestinal disease, cardiovascular disease, osteoporosis and aging.”

Ghrelin is a hormone produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas that stimulates hunger.[1] Ghrelin levels increase before meals and decrease after meals. It is considered the counterpart of the hormone leptin, produced by adipose tissue, which induces satiation when present at higher levels(ref).”  “The hypothalamus in the brain is another significant source of ghrelin; smaller amounts are produced in the placenta, kidney, and pituitary gland(ref).”

“Ghrelin’s activity in modulating feeding behavior and energy balance are best explained by the presence of ghrelin receptors in areas of the hypothalamus long known to be involved in appetite regulation. Receptors are also found concentrated in other areas of the brain, including the hippocampus and regions known to be involved in reward systems (e.g. tegmental area); indeed, ghrelin appears to activate some of the same circuits that are involved in drug reward, which may also be related to this hormone’s effects on appetite(ref).”

“At least two major biologic activities have been ascribed to ghrelin:  Stimulation of growth hormone secretion: Ghrelin, as the ligand for the growth hormone secretagogue receptor, potently stimulates secretion of growth hormone. The ghrelin signal is integrated with that of growth hormone releasing hormone and somatostatin to control the timing and magnitude of growth hormone secretion. – Regulation of energy balance: In both rodents and humans, ghrelin functions to increase hunger though its action on hypothalamic feeding centers. – (ref)

Ghrelin is a key actor in the hypothalamic melanocortin system.  As an important part of that model, the gut hormone ghrelin is believed to inform the brain about energy availability and has been shown to increase adiposity, raise blood pressure and promote hyperglycemia(ref). The overwhelming majority of ghrelin’s effects on metabolism are mediated via CNS circuits, with the hypothalamic melanocortin system arguably being its most important direct target(ref)3. In turn, the melanocortin system is an essential and potent regulator of body adiposity, glucose metabolism and blood pressure(ref). Furthermore, mutations of melanocortin receptors are strongly correlated with human obesity(ref) and alterations in cholesterol transport are a common occurrence in obesity and the metabolic syndrome(ref). We hypothesized that a gut-brain axis integrates all of the primary physiological components known to be affected in the metabolic syndrome, that, in addition to regulating glucose homeostasis, blood pressure, food intake and body weight, it also likely controls cholesterol metabolism. We found that a gut-brain axis including ghrelin, glucagon-like peptide 1 (GLP-1) and the central melanocortin system directly regulates the hepatic synthesis and re-uptake of cholesterol(ref).”

Ghrelin and growth hormone secretion

The 2000 paper Preliminary evidence that Ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans was one of the first to point to actions of ghrelin going beyond simple appetite-regulating and metabolic effects. “In conclusion, this preliminary study shows that Ghrelin exerts a strong stimulatory effect on GH (growth hormone) secretion in humans releasing more GH than GHRH.” Of course, growth hormone exercises multiple effects of its own. “Growth hormone (GH) is a protein-based poly-peptide hormone. It stimulates growth, cell reproduction and regeneration in humans and other animals. It is a 191-amino acid, single-chain polypeptide hormone that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior pituitary gland(ref).”

Ghrelin, hunger and obesity

The 2001 publication Minireview: Ghrelin and the Regulation of Energy Balance—A Hypothalamic Perspective  “The first published evidence for the involvement of ghrelin in the regulation of appetite was provided by Ghigo and co-workers (ref)). They described that 3 out of 4 healthy volunteers spontaneously reported hunger following ghrelin administration as a “side effect” in a clinical study analyzing GH release (ref). This hunger-inducing effect of ghrelin has now been confirmed in two more studies, where, again, 3 out of 7 (33) and 9 out of 11 individuals report hunger as the only sensation after ghrelin injection –. A large number of animal studies added strength to the argument that ghrelin is involved in the regulation of energy balance. For example, exogenous ghrelin induces adiposity in rodents by stimulating an acute increase in food intake, as well as a reduction in fat utilization –. Adipogenic as well as orexigenic effects of ghrelin are independent from its ability to stimulate GH secretion — and are most likely mediated by a specific central network of neurons that is also modulated by leptin –.” 

The 2007 article Meal suppression of circulating ghrelin is normalized in obese individuals following gastric bypass surgery examines ghrelin levels in obese individuals, indicating effects of gastric bypass surgery.  “Design:  Cross-sectional study with repeated blood samples in 40 subjects after 14 h of prolonged overnight fasting followed by a standardized mixed meal (770 kcal).  Subjects: Twenty men and 20 women were included: 10 middle-aged morbidly obese (body mass index (BMI) 43.9 3.3 kg/m2), 10 middle-aged subjects who had undergone RYGBP (Roux-en-Y gastric bypass surgery) at the Uppsala University Hospital (BMI 34.7 5.8 kg/m2), 10 middle-aged non-obese (BMI 23.5 2.2 kg/m2) and 10 young non-obese (BMI 22.7 1.8 kg/m2).  Measurements: Ghrelin, glucose and insulin levels were analyzed pre- and postprandially. Results: In the morbidly obese, ghrelin concentrations were lower in the morning than in the RYGBP group and did not change following the meal. In the RYGBP group, fasting ghrelin levels fell after meal intake and showed similar suppression as both age-matched and young non-obese controls. The RYGBP surgery resulted in an increased meal-induced insulin secretion, which was related to the degree of postprandial ghrelin suppression.  Conclusion: The present study demonstrates low circulating concentrations of ghrelin and blunted responses to fast and feeding in morbidly obese subjects. Marked weight reduction after RYGBP at our hospital is followed by a normalization of ghrelin secretion, illustrated by increased fasting levels compared to the preoperative obese state and regain of meal-induced ghrelin suppression.”

The 2010 publication Plasma ghrelin levels and polymorphisms  of ghrelin gene in Chinese obese children and adolescents indicates “AIM: To evaluate the role of fasting plasma ghrelin levels [ln(ghrelin)] and polymorphisms of ghrelin gene in Chinese obese children. METHODS: Genotyping for ghrelin polymorphism was performed in 230 obese and 100 normal weight children. Among them, plasma ghrelin levels were measured in 91 obese and 23 health subjects. RESULTS: (1) Bivariate correlation analysis showed the ln(ghrelin) was inversely correlated with abnormality of glucose metabolism (r = -0.240, P = 0.023). Stepwise multiple regression analysis showed that abnormality of glucose metabolism was an independent determinant of plasma ghrelin levels (P = 0.023). — CONCLUSION: Ghrelin is associated with obesity in childhood, especially associated with the glucose homeostasis. Lower ghrelin levels might be a result of obesity, but not a cause of obesity.  –” 

The 2009 publication Ghrelin and growth hormone secretagogues, physiological and pharmacological aspect looks at the possibility of pharmacological interference with expression of ghrelin as a strategy to control appetite and obesity.  “At least theoretically ghrelin receptor antagonists could be anti-obesity drugs, as blockers of the orexigenic signal from the gastrointestinal tract to the brain. Inverse agonists of the ghrelin receptor, by blocking the constitutive receptor activity, might lower the set-point for hunger between meals.”   

The 2006 publication Ghrelin and the short- and long-term regulation of appetite and body weight came to a similar conclusion. “Chronic ghrelin administration increases body weight via diverse, concerted actions on food intake, energy expenditure, and fuel utilization. Congenital ablation of the ghrelin or ghrelin-receptor gene causes resistance to diet-induced obesity, and pharmacologic ghrelin blockade reduces food intake and body weight. Ghrelin levels are high in Prader-Willi syndrome and low after gastric bypass surgery, possibly contributing to body-weight alterations in these settings. Extant evidence favors roles for ghrelin in both short-term meal initiation and long-term energy homeostasis, making it an attractive target for drugs to treat obesity and/or wasting disorders.” 

Ghrelin, inflammatory diseases and NF-kappaB 

In a number of previous blog entries and in my treatise I have written about inhibition of expression of NF-kappaB as a strategy for controlling inflammatory diseases and perhaps even for life extension(ref)(ref)(ref)(ref).  It appears that ghrelin is an inhibitor of NF-kappaB and helps control at least some inflammatory diseases.  The 2007 publication Ghrelin attenuates sepsis-induced acute lung injury and mortality in rats reports “Our study has shown that plasma levels of ghrelin, a stomach-derived peptide, are significantly reduced in sepsis, and that ghrelin administration improves organ blood flow via a nuclear factor (NF)-kappaB-dependent pathway. — Ghrelin administration restored pulmonary levels of ghrelin, reduced lung injury, increased pulmonary blood flow, down-regulated proinflammatory cytokines, inhibited NF-kappaB activation, and improved survival in sepsis. — CONCLUSIONS: Ghrelin can be developed as a novel treatment for severe sepsis-induced ALI. The protective effect of ghrelin is mediated through inhibition of NF-kappaB.” 

Ghrelin and radiation injury

A 2009 paper Human ghrelin ameliorates organ injury and improves survival after radiation injury combined with severe sepsis points to another potential role for ghrelin.  “Administration of human ghrelin attenuated tissue injury markedly, reduced proinflammatory cytokine levels, decreased tissue myeloperoxidase activity, and improved survival after RCI. Furthermore, elevated plasma levels of norepinephrine (NE) after RCI were reduced significantly by ghrelin. However, vagotomy prevented ghrelin’s beneficial effects after RCI. In conclusion, human ghrelin is beneficial in a rat model of RCI. The protective effect of human ghrelin appears to be attributed to re-balancing the dysregulated sympathetic/parasympathetic nervous systems.”

And, a  2010 paper Ghrelin as a novel therapy for radiation combined injury indicates “In this review, we describe briefly the pathological consequences of ionizing radiation and provide an overview of the animal models of radiation combined injury. We highlight the combined radiation and sepsis model we recently established and suggest the use of ghrelin, a novel gastrointestinal hormone, as a potential therapy for radiation combined injury.”

Ghrelin and aging

Expression of ghrelin changes with aging and ghrelin expression affects the aging process.  It contributes to energy balance.  According to the 2010 publication Thermoregulation, energy balance, regulatory peptides: recent developments, “Some peripheral peptides (e.g. leptin, insulin, ghrelin) acting at either peripheral or cerebral sites also contribute to the regulation of energy balance. The prevailing thermoregulatory status, the substances or neural signals representing actual feeding vs. established nutritional states, and the aging process may modify the expression and/or activity of peripheral and central peptides and peptide receptors.” 

Another 2010 publication concludes “In healthy elderly people relatively large amounts of fat increase the satiety signal from GLP-1 and lower the acylated to desacylated ratio of ghrelin, consequently decreasing hunger. This condition may lead to a reduction in calorie intake.” 

Yet-another 2010 e-publication Impaired postprandial response of active ghrelin and prolonged suppression of hunger sensation in the elderly has related findings.  “RESULTS: Our results showed that older participants felt postprandially less hungry and more full. Although basal levels were not significantly different, active and total ghrelin levels declined postprandially only in the younger study participants. Highly significant differences between the two age groups were shown for the changes of the area under the curve for active ghrelin (p = .024). CONCLUSIONS: Our study demonstrates for the first time that differences in hunger and satiety sensations in relation to age are paralleled by a substantially different response of acylated and total ghrelin, that is, the absence of a postprandial decline in ghrelin levels.”


Research into ghrelin and its related pathways and activities appears to be mostly in the last 10 years and definitely accelerating.  Part of the impetus is the current concern with obesity.  It is likely that therapies will be proposed for a number of disease conditions based on manipulation of ghrelin.  At present, however, there are only hints of anti-aging interventions based on manipulation of ghrelin.  I would not be surprised to see publications on this topic appearing in the coming year or so. 

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at and an extensive site of my art at Please note that I have recently changed my mailbox to
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One Response to Ghrelin hunger, obesity and aging

  1. Muchacho says:

    Hi there, a very good read and it sometimes just takes someone to post something like this to make me realise where I’ve been going wrong! Just added the site to my bookmarks so will check back now and then. Cheers.

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