Lifelong Stimulation of the Ghrelin Receptor Modestly Increases Mouse Life Span

The evidence of recent years from studies of calorie restriction and intermittent fasting might lead one to suspect that the length of time spent being hungry is an important determining factor, on a par with calorie intake. In the course of physiological hunger, a range of signaling processes kick in and cell behavior changes in response. Is this important in distinction to the lower level nutrient sensing processes inside cells? So much changes in the course of fasting or calorie restriction that it is challenging to pick out the most relevant mechanisms.

One of the noteworthy mechanisms of hunger is ghrelin signaling. In this study, researchers stimulate the ghrelin receptor using a suitable small molecule for much of the lifespan of mice, and observe the results. The overall extension of life span is a quarter of that produced by calorie restriction, and so we might draw some conclusions from that as to the relative importance of hunger in the benefits resulting from the practice of calorie restriction or fasting. Interestingly, the short term weight gains observed in mice given this ghrelin receptor agonist in the past don't appear in this long term study, in which the controls are the heaver animals. This is possibly because the researchers didn't allow the mice to overeat, by pairing their consumption with that of the untreated control animals.

The effect of a pharmaceutical ghrelin agonist on lifespan in C57BL/6J male mice: A controlled experiment

Of the well-studied effects on lifespan in mouse models, detailed mechanisms underlying the health and longevity benefit of caloric restriction (CR) are still being investigated despite some limitations on the practical applications to humans. A major limitation of animal models is that they cannot self-report hunger or other physiological sensations that would inform mechanistic work. Since ghrelin was first described and noted as a growth hormone secretagogue receptor (GHS-R) agonist, much study has focused on the effects on hunger and appetite regulation along with other aspects of energy balance.

Investigators examining effects on cognition in mouse models have posited that the mechanism may involve interoceptive cues or signaling, rather than reduced energy intake per se. In those studies, oral administration of a ghrelin agonist (LY444711, an orally active compound that binds with high affinity to and is a potent activator of the growth hormone secretagogue receptor 1a [GHS-R1a] receptor, reduces Alzheimer's disease pathology and improves cognition in the APP-SwDI mouse model. Treatment also reduced levels of amyloid beta (Aβ) and neuroinflammation (as measured by microglial activation) at 6 months of age compared to controls, like the effect seen in the 20% CR group (gp) but with no significant difference in body weight (BW) or percentage body fat.

LY444711 binds to the human ghrelin receptor (GHS-R1a) and is a functional agonist. This agonist produced orexigenic behavior in rodents, including stimulated energy intake (food consumption is 40% than controls at 10 mg/kg and 50% greater than controls at 30 mg/kg dose), positive energy balance (23% greater BW with 2 weeks treatment at 10 mg/kg), acute higher respiratory quotient (RQ) with increased dose, and increased adiposity (greater fat mass but no significant difference in lean mass). The authors conclude this substance is orally active with an extended half-life relative to native ghrelin.

Despite various studies on ghrelin effects on food intake and body composition, studies of ghrelin agonists on lifespan-extending effects in rodent models are lacking. We tested the hypothesis that a pathway related to perceived hunger, as induced by an oral, exogenously administered orexigenic agent (i.e., a synthetic ghrelin agonist), would affect lifespan in mice. Mice aged 4 weeks were allowed to acclimate for 2 weeks prior to being assigned (N = 60/group). Prior to lights off daily, animals were fed LY444711 or a placebo control until death. Treatment (GhrAg) animals were pair-fed daily based on the group mean food intake consumed by controls (ad libitum feeding) the prior week. Results indicate an increased lifespan effect for GhrAg versus controls, which weighed significantly more than GhrAg (adjusted for baseline weight). Further studies are needed to determine the full scope of effects of this ghrelin agonist, either directly via increased ghrelin receptor signaling or indirectly via other hypothalamic, systemic, or tissue-specific mechanisms.