The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 11 No. 3 • May 2008


EMERGING SCIENCE

Ghrelin: A Mere Hormonal Appetite Stimulant or a
Possible Anti-Aging Molecule

There are efforts being made by pharmaceutical companies to develop inhibitors or blockers of ghrelin because of its role in appetite stimulation. Indeed, studies have shown a good correlation between plasma ghrelin and corresponding food intakes or hunger.1 Moreover, an experimental ghrelin receptor blocker was shown to attenuate food intake and weight gain in mice.1 However, whether such suppression is a good idea might depend on whether it suppressed the beneficial effects of ghrelin, as we discuss below, including the possibility that ghrelin has anti-aging effects. Following the section on “The Ghrelin Receptor as a Possible Site for Anti-Aging Effects,” we also discuss the possibility that octanoic acid, the principal fatty acid found in MCTs (medium-chain triglycerides), might play a role in regulating the activity of ghrelin.

The ghrelin response to a meal is attenuated in obese individuals compared to young persons,1 suggesting that, like leptin, another hormone that regulates food intake, obese individuals may be “ghrelin-resistant.”

Interestingly, although ghrelin is an appetite-stimulating hormone, and eating a carbohydrate-rich meal reduces ghrelin levels following the meal, eating a protein-rich, low-carbohydrate meal actually increases ghrelin levels.1 Although the data are inconsistent, it appears that protein and carbohydrates are satiating to a similar degree. It is thought that insulin release may be what causes ghrelin levels to fall after a carbohydrate-rich meal.2 Similarly to normal-weight subjects, ghrelin levels increase after a protein-rich meal in obese subjects, but to a lesser extent than in normals.1

It appears too that a carbohydrate-rich meal enriched with fiber (arabinoxylan, a soluble fiber) that caused only a tendency (P=0.065; significance would require P≤0.05) toward lower insulin levels (though not glucose levels) can cause an increase in postprandial ghrelin levels3 in subjects with normal glucose regulation. (The authors doubt that the effect was mediated by insulin, however. We are not so sure, as P=0.065 is not far from 0.05, which would show significance.) Whether this is a real effect and whether it applies to other types of fiber remain to be determined.

Whether it is a good idea to suppress ghrelin in the obese to decrease appetite is, in our judgment, questionable, as there are data indicating that ghrelin has potentially important beneficial effects, including anti-inflammatory activity and thymus-protective (hence, improved immune activity) effects. Another paper6 proposes that ghrelin receptor agonists may be effective for anti-aging intervention. The ghrelin receptor is a powerful growth hormone secretagogue, that is, it causes growth hormone release when stimulated by ghrelin. The evidence indicates that ghrelin is important in regulating the growth hormone/insulinlike growth factor axis.

Ghrelin Effects on Immunity

A recent paper reports that ghrelin is expressed in the thymus gland, and in immune cells it regulates T-cell activation and inflammation.4 The authors of this paper found that ghrelin and ghrelin receptor expression within the thymus decline with age in mice. Infusion of ghrelin into 14-month old-mice resulted in significantly improving the age-associated decline in thymus architecture and thymocyte numbers. Conversely, they report, ghrelin and ghrelin receptor-deficient mice had enhanced age-associated thymic involution.

Ghrelin as an Anti-Inflammatory Molecule Could Protect Against Atherosclerosis

Another recent paper5 reports, in a cell culture study of human umbilical vein endothelial cells (HUVECs), that ghrelin inhibited both basal and tumor necrosis factor-alpha-induced proinflammatory cytokine release. They also found that intravenous administration of ghrelin to rats inhibited endotoxin-induced proinflammatory cytokine production. Moreover, ghrelin inhibited the cytokine release in the HUVECs in response to hydrogen peroxide. The authors suggest that “These novel anti-inflammatory actions of ghrelin suggest that the peptide could play a modulatory role in atherosclerosis, especially in obese patients, in whom ghrelin levels are reduced.”

The Ghrelin Receptor as a Possible Site for Anti-Aging Effects

A recent paper6 suggests that agonists of the ghrelin receptor show potential for anti-aging intervention. First, the authors report that “the weight of the evidence suggests that, in humans, aging is associated with reduced ghrelin production as well as ghrelin resistance.” This decline may be a cause of the decrease in pulsatile release of growth hormone, as ghrelin regulates the latter.

The authors further report that, although ghrelin is involved in appetite stimulation, it is also “localized to areas of the central nervous system that regulate mood, memory, and learning.” They report that an earlier experiment by a different group had found that “Chronic administration of the ghrelin mimetic MK-0677 to elderly humans produced a sustained rejuvenation of the GH/IGF-1 axis, suggesting that MK-0677 compensates for a deficit in endogenous ghrelin signaling.” They also reported that “in postmenopausal women, treatment [with MK-0677] for up to 18 months, produced increases in bone mineral density.” They also note that “. . . hyperstimulation of the GH/IGF-1 axis [by the ghrelin mimetic] was prevented by endogenous regulatory feedback loop.”

With respect to health span (length of the healthy active part of life), the authors report that in elderly women, “the 5-year mortality can be predicted according to the IGF-1/IL-6 ratio” and propose that, since ghrelin can decrease IL-6 and increase IGF-1, it may extend health span. They also report that in a study done by others, administration of ghrelin to rats caused increased expression of the mitochondrial UCP2 (uncoupling protein 2); UCP2 has been proposed to reduce the production of reactive oxygen species in the mitochondria as well as promoting the burning of fats.6b

Also very interesting, the authors found that ghrelin could amplify dopamine signaling, which ordinarily declines during aging, in a cell culture study.

Ghrelin Activation by Octanoate, the Major Fatty Acid in Medium-Chain Triglycerides (MCTs)

Finally, there have been a number of recent reports5,6 that suggest that octanoylation (chemical combination with octanoate) is critical for ghrelin’s anti-inflammatory effects in endothelial cells and is required for its growth hormone-releasing action via the growth hormone secretagogue receptor. We speculate that the consumption or supplementation of medium-chain triglycerides, which supplies octanoate (the most plentiful fatty acid in MCTs), might increase the activity of ghrelin. This exciting possibility will remain unclear, however, until appropriate studies are done. In the meantime, we use Durk & Sandy’s medium-chain triglycerides on our salads and in baked and other cooked food (but not fried, as MCTs cannot tolerate such high temperatures), because MCTs are mostly metabolized for energy rather than stored as body fat.

References

  1. Erdmann et al. Ghrelin response to protein and carbohydrate meals in relation to food intake and glycerol levels in obese subjects. Regulatory Peptides 135:23-9 (2006).
  2. Blom et al. Ghrelin responses to carbohydrate-enriched breakfast is related to insulin. Am J Clin Nutr 81:367-75 (2005).
  3. Mohlig et al. Arabinoxylan-enriched meal increases serum ghrelin levels in healthy humans. Horm Metab Res 37:303-8 (2005).
  4. Dixit et al. Ghrelin promotes thymopoiesis during aging. J Clin Invest 117(10):2778-90 (2007).
  5. Li et al. Ghrelin inhibits proinflammatory responses and nuclear factor-kappaB activation in human endothelial cells. Circulation 109:2221-6 (2004).
  6. Smith et al. Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging. Ann NY Acad Sci 1119:147-64 (2007).
    6b. Pecqueur et al. Uncoupling protein-2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis-derived pyruvate utilization. FASEB J 22:9-18 (2008).
  7. Zhu et al. On the processing of proghrelin to ghrelin. J Biol Chem 281(50):38867-70 (2006).

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